solubility challenges - informa...

JULY 2015 Volume 27 Number 7

Solubility ChallengesUnlocking a Drug’s Potential

DRUG DEVELOPMENT

Market Access in France

QA/QC

Data Integrity

DRUG DELIVERY

Colon Targeting

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Cover: Creative Crop/Getty ImagesArt direction: Dan Ward

July 2015

Features

COVER STORY

20 Solving Poor Solubility to Unlock a Drug’s Potential

Modern methods and modelling offer a better way

to understand solubility issues and solve today’s

complex formulation challenges.

QA/QC

26 A Risk-Based Approach to Data Integrity

Heightened regulatory scrutiny of data integrity

highlights the need for comprehensive procedural

reviews and strategies for managing mission-critical

information.

DRUG DELIVERY

34 Mission Possible: Targeting Drugs to the Colon

Prodrugs and drug-delivery systems controlled by

time, pH, and osmosis are being used to prevent

drug degradation in the stomach and small intestine

and ensure drug release in the colon.

PharmTech.com

Columns and Regulars

5 Guest Editorial CRS Meets in Edinburgh

6 Drug Development Market Access Outlook for France

12 EU Regulatory Watch Unravelling the Complexity of EU’s ATMP Regulatory Framework

16 US Regulatory Watch Breakthrough Drugs Raise Development and Production Challenges

18 Outsourcing Review CDMOs Cautiously Address Expansion

30 API Synthesis & Manufacturing Lack of Expertise Hinders Adoption

of Continuous API Synthesis

44 Troubleshooting Testing the Stability of Biologics

47 Packaging Forum Ensuring Correct Tablet Count

50 Ad Index

Peer-Reviewed36 Beyond the Blink: Using In-Situ Gelling

to Optimize Opthalmic Drug Delivery

Delivery systems that allow drugs to be administered

as liquids, but form gel within the eye, promise to

improve efficacy and patient compliance.

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GUEST EDITORIAL

CRS Meets in Edinburgh

The Controlled Release

Society (CRS) is

holding its 42nd Annual

Meeting in Edinburgh,

Scotland on 26–29

July. We are expecting

approximately 1500

attendees at this event,

which is spearheaded by

strong science and a programme that allows

members social time to network.

Although known as CRS, we often use the

phrase “delivery science and technology” to

describe our field. Technologies can take a

drug that has to be orally administered two to

six times a day and convert it to an improved

dosage form that is taken only once a day.

A drug that requires daily injections can

also be developed into a formulation that is

administered only once a month. These are

two examples of the time element of delivery.

Formulations and technologies also

allow for spatial delivery. This local delivery

can be accomplished as easily as a direct

injection into the eye or brain, for example.

Alternatively, a drug can be linked to an

antibody, delivered systematically, and the

antibody then targets cancer cells for the

oncology payload. In a recent case of local

delivery providing systemic administration,

sophisticated device and formulation have

allowed the delivery of insulin particles

into the lung, where the insulin is absorbed

into the bloodstream, eliminating the need

for some injections in the treatment of

diabetes.

Like other societies, ours has changed,

in particular over the past decade. People

have become increasingly accustomed to

free content. Niche meetings are becoming

more prevalent. CRS continues to have a

membership that remains engaged, which I

attribute to the following reasons:

• We provide an effective forum for and

access to strong fundamental delivery

science.

• We continue to have luminaries in our field

as speakers, collaborators, and mentors.

• We foster dialogue between scientists,

both established and emerging.

• We focus on creating networking—

scientific or social collisions—be they

between academicians and industrialists,

scientists and engineers, or amongst

people from various countries.

• We nurture our young scientists with

special sessions and events planned for

our next generation of leaders.

While we embrace newer ways of

information exchange, there is still nothing

as enjoyable and productive as that face-to-

face scientific discussion. We look forward to

a multitude of those in Edinburgh, and trust

some will be held over a dram of whisky.

Arthur J. Tipton, PhD

President and CEO of

Southern Research Institute

President of CRS



Michael J.

Kuchenreuther, PhD

is a research analyst for

Numerof & Associates.

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DRUG DEVELOPMENT: FRANCE

Market AccessOutlook for FranceWith the French pricing and reimbursement policies becoming increasingly stringent,

pharmaceutical manufacturers must adapt their drug development and commercial strategies

if they want to secure premium pricing for their new products.

In France, the pricing and reimbursement landscape

is certainly changing. Take for instance the case of

Gilead’s Hepatitis C blockbuster, Sovaldi. According to

clinical trial data, 90% of patients for whom this drug

is indicated for are for all intents and purposes cured

upon treatment completion. A few years ago, Sovaldi

would have likely been awarded a premium price in

France, which has traditionally only considered the

therapeutic benefit of new drugs to inform pricing

decisions. It would have also entered the French

market at a high price point relative to other European

Union Five markets, including the cost-conscientious

United Kingdom.

However, the need for the government to continue

providing universal healthcare coverage to an aging

population, along with increasing drug prices and

shrinking budgets, recently drove the country to

introduce pharmacoeconomic analysis as part of its

pricing process. Due in part to a more economically

focused health technology assessment process,

in late 2014, the French government was able to

get Sovaldi at the lowest list price in Europe. The

government also secured a volume-based tax and

performance-based discount in exchange for 100%

reimbursement. Based on the limited number

of pharmacoeconomic analyses that have been

published to date, manufacturers can expect to face

tougher negotiations with the pricing committee, with

a final price potentially below expectations.

In addition to pricing pressures, manufacturers face

other challenges in France including the government’s

mounting focus on driving the use of generic

drugs and biosimilars, which may restrict market

growth. This article explores some of the recent

developments in the French pharmaceutical market,

identifies pricing and reimbursement challenges, and

discusses strategies manufacturers should consider

for sustainable success.

Healthcare spending regulation in FranceAs in most other developed markets, budget and cost

control have been key issues in France. The country’s

compulsory and uniform health insurance scheme

has faced large deficits over the past 20 years.

Economic downturns and the growing healthcare

needs of an aging population have only amplified the

government’s focus on driving down healthcare costs

to ensure sustainability.

Successive reforms have led to a decrease in

government-sponsored reimbursement rates for

select populations and/or types of care, leaving some

patients with higher copayments and coinsurance.

While more than 90% of the country’s population has

supplemental health insurance, reimbursement of

copayments through private insurers has recently

been discontinued for certain types of prescription

drugs, doctor visits, and ambulance transport (1, 2).

Decreased reimbursement is just one mechanism

through which healthcare spending has been

regulated. Other mechanisms include a reduction in

the number of acute-care hospital beds, the removal

of more than 600 drugs from public reimbursement

over the past several years, the monitoring and

sanctioning of medical practitioners for prescribing

too many drugs, changes to its health technology

assessment (HTA) process, and promoting uptake

of generic and over-the-counter medicines (3). The

French Government shows no sign of slowing down

its health reform efforts, as it hopes to make €10

billion in additional cuts over the next three years (3).

The French pharmaceutical market—Overview, key trends, and developmentsPricing and reimbursement in France.

Reimbursement for pharmaceuticals is determined

primarily at the national level. Following market

authorization from the European Medicines Agency

(EMA), a drug is assessed by the independent health

authority, Haute Autorité de Santé (HAS).

In France, HTAs have traditionally only considered

the therapeutic benefit of new drugs to inform pricing

and reimbursement decisions. Consequently, the key

requirement for obtaining maximum reimbursement

and a premium price has historically been innovation.

However, since the formal introduction of drug cost-

effectiveness evaluation in October 2013, therapeutic

benefit remains a prerequisite for optimal market

access but is no longer sufficient on its own.

HTAs still begin with determination of a product’s

“medical benefit” (SMR—Service Médical Rendu)


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Drug Development


based on the following criteria—

efficacy and safety; existence or

absence of therapeutic alternatives;

severity of the disease; treatment

type, specifically preventative,

curative or symptomatic; and public

health impact.

In a separate, but concurrent

process, a new product is also

measured against a comparator drug

to determine the “improvement of

medical benefit” (ASMR—Amélioration

du Service Médical Rendu). In France,

the method for assigning a comparator

is less rigidly defined than in other

countries. For instance, in Germany,

the comparator is defined by the

government, while in France, the

manufacturer sets the comparator

but must provide justification (4). The

ASMR rating, from I (superior) to V

(inferior), is generally clearly correlated

to a relatively narrow range of price

premiums or discounts.

Nonetheless, as highlighted

above, in late 2013, the Committee

for Economic Evaluation and Public

Health (CEESP), a separate group

under HAS, was mandated to

also consider pharmacoeconomic

evidence for new technologies that

claim a high ASMR (I–III) and that

are expected to have sales in excess

of €20 million. By the end of 2014, the

CEESP had completed 12 economic

evaluations, four of which have

been made publically available (5).

These evaluations include cost-

effectiveness/cost-utility analyses,

health economic modelling, and

sensitivity/scenario analysis, all of

which feed directly into the decision-

making process of the pricing

committee (6).

While guidelines used for economic

assessments in other countries such

as the UK are descriptive, detailed,

and prescriptive, the ones published

by HAS are prominently non-

exhaustive and non-definitive, leaving

researchers with more flexibility to

conduct these evaluations (7). One

aspect of the pharmacoeconomic

evaluation that remains quite unclear

is the financial threshold HAS deems

to be acceptable when looking at

the conclusions of CEESP’s analyses.

Currently, there is no established

threshold in terms of incremental

cost per quality-adjusted life year

(QALY) or per life-year gained.

Potential future changes to

the pricing and reimbursement

process. Despite the recent

introduction of pharmacoeconomic

analyses, innovation and clinical

effectiveness remain the sole

determinants of product adoption in

France. However, as the government

continues to explore mechanisms

for reducing healthcare expenditures

and increasing healthcare value,

manufacturers should expect

discussions around future changes

to the pricing and reimbursement

process to continue. For instance,

in a recent report, the General

Inspectorate of Social Affairs

highlights the introduction of

economic evaluations into the pricing

process and discusses how cost

effectiveness analyses could also

be considered in national coverage

decisions and in defining specific

reimbursement rates as seen in

other countries like the UK (8). With

the commission currently finding it

difficult to justify the use of a fixed

threshold to refuse a new product,

a dramatic shift is unlikely in the

near future but remains a possibility

over time.

Beyond the role of cost

effectiveness analyses, changes

to the broader pricing and

reimbursement system are also

being considered. In 2012, the HAS

proposed to replace SMR and ASMR

by a single index called the Relative

Therapeutic Index (ITR), a new

assessment tool which was to place

greater emphasis on comparator

and clinical endpoint relevance as

well as on the validity of studies

aimed to demonstrate superiority

and non-inferiority (9). While the

ITR determination process failed

to gain enough traction among

policymakers to lead to changes, the

government continues to explore

new, stricter methods of deciding on

reimbursement rates and pricing. In

fact, the French Ministry of Health

has reportedly commissioned a work

group to review current modalities for

drug assessments (10).

Use of generic drugs. France has

historically been a strong market

for branded drugs. In 2008, generic

drugs accounted for only 21.7% of the

pharmaceutical market in terms of

volume. As of 2013, the rate climbed

to 30.2%, largely due to measures

introduced to stimulate generic

prescription by physicians, generic

substitution by pharmacists, and

generic acceptance by patients (11).

Generic-drug prescribing in France,

however, still lags behind other

countries. To address this issue,

France’s health minister, Marisol

Touraine, presented a national plan

to increase generic prescription by

five percentage points by removing

“the remaining obstacles to the use

of generic drugs for all situations

where such use is possible” (12).

Specific elements of this plan include

a national advertising campaign to

boost public confidence, the provision

of additional payments to physicians

and pharmacists linked to generic-

drug prescription, mandates for

hospitals to comply with a generic

prescribing rate, and interventions

to monitor physicians’ markings of

prescriptions as non-substitutable.

With biologicals representing more

than 25% of spending on drugs in

France, legislation has also focused

on promoting biosimilars as a means

of reducing expenditures. In 2014,

France became the first European

country to formally allow substitution

of biosimilars under certain

conditions (13). Since 2007, the

French market has not necessarily

been a leader in biosimilar

penetration relative to other EU

countries, but volume in terms of

sales has consistently increased each

year. The recent launch of Celltrion’s

Remisura, the world’s first biosimilar

monoclonal antibody indicated for

multiple chronic diseases, taken

together with looser regulations

on how biosimilars can be used,

have many feeling optimistic about

the cost-savings potential of these

follow-on biologics moving forward.

Implications for manufacturersThe French government remains

committed to reducing growth in

healthcare costs as evidenced by

recent legislation and the introduction

of cost-effectiveness evaluations

in pricing decisions of select new

products. While the country’s

pharmaceutical industry has long

been one of the biggest in both

Europe and the world, these cost-


Drug Development

containment and other measures

have serious implications for

manufacturers and their go-to-market

strategy. The market is forecast to

grow at a tepid compound annual

growth rate (CAGR) of 0.7% from

US$46.2 billion in 2014 to US$48.2

billion by 2020 (14).

Some manufacturers may

prefer to wait and see if France

adopts more stringent pricing and

reimbursement policies for new

therapeutic products—either through

more rigorous clinical effectiveness

requirements or through the use of

cost-effectiveness analysis to guide

coverage decisions—before changing

their development and commercial

strategies. However, global markets,

including France, are already

showing clear signs that incremental

innovations will be closely scrutinized

and that unless there is clearly

demonstrated value, new products

are unlikely to command premium

pricing. Even doing so may not be

enough to protect products from

additional scrutiny over price and

access restrictions, as seen with

Sovaldi.

With generic drug use expected to

rise and as “generics as standard-of-

care” settles in, biopharmaceutical

companies will need a higher

degree of clinical and economic

differentiation to be successful (14).

Business models need to shift from

being product-centric to patient

centric (15). Clinical trials must focus

on endpoints that matter to patients,

their caregivers and their families, as

opposed to surrogate endpoints that

are not validated.

The message manufacturers

are delivering to key stakeholders

also needs to change. Large data

packages and exhaustive global

value dossiers deliver much-

needed evidence but do not make

a compelling case in isolation.

“What is your technology’s benefit

to the patient population and other

stakeholders in that particular

market?” This question needs to be

front and center of all discussions.

Manufacturers that understand

specific pain points can design

products or services that address

these issues and package those

benefits into meaningful value

stories.

While product innovation remains

the key determinant of coverage

in France, innovative pricing

mechanisms, such as risk sharing,

outcomes-based contracting and

managed entry agreements, are

becoming more important for optimal

pricing. This trend is seen in other

countries as well (16). In fact, Celgene

recently committed to the French

Government on the effectiveness of

their multiple myeloma drug Imnovid

in exchange for a higher price (17).

The agreement required Celgene

to build a registry for collecting

real-world efficacy and safety

data. Discounts and price volume

agreements have been used in this

market for several years; however,

the growing focus on value has

created a greater appetite among

decision makers for more productive

sharing of risk with manufacturers.

Here, understanding the economic

and clinical value delivered by a given

product is crucial in determining

whether a risk-based agreement is

the right strategy, and if so, how an

arrangement should be structured.

AcknowledgementThe author would like to thank Dr.

Marc Bardou for his contributions to

this article.

References1. M. Cabral and N. Mahoney, Externalities

and Taxation of Supplemental

Insurance: A Study of Medicare and

Medigap, https://economics.stanford.

edu/files/Cabral12_10.pdf, accessed 11

June 2015.

2. I. Durand-Zaleski, The French

Healthcare System, 2014 in The

Commonwealth Fund, 2014

International Profiles Of Healthcare

Systems, January 2015.

3. The Local, “The key reforms of France’s

healthcare bill,” Press Release, 31

March 2015.

4. A. Szerb and P. Kanavos, Health

Technology Assessment of Cancer

Drugs in France and Germany:

Commonalities and Differences in

the Value Assessment of Medical

Technologies, The London School

of Economics and Political Science,

January 2015.

5. A. Ackermann, The impact of

pharmacoeconomic analyses and

efficiency opinions in France, 25

March 2015, http://blog.ihs.com/

the-impact-of-pharmacoeconomic-

analyses-and-%E2%80%9Cefficiency-

opinions%E2%80%9D-in-france,

accessed 11 June 2015.

6. Haute Autorité de santé, Choices in

Methods for Economic Evaluation,

October 2012, www.has-sante.fr/

portail/upload/docs/application/

pdf/2012-10/choices_in_methods_for_

economic_evaluation.pdf, accessed 22

June 2015.

7. M. Massetti et al., Journal of Market

Access and Health Policy, online doi.

org/10.3402/jmahp.v3.24966, March

2015.

8. Inspection Générale des Affaires

Sociales, Medical and economic

evaluation in health, December 2014.

9. C. Remuzat, M. Toumi, and B. Falissard.

Journal of Market Access and Health

Policy, online doi.org/10.3402/jmahp.

v1i0.20892, August 2013.

10. Fravimed, A modification of the French

“SMR/ASMR” system is necessary, but

is not urgent, 31 March 2015, www.

fravimed.com/news/a-modification-

of-the-french-smr-asmr-system-is-

necessary-but-is-not-urgent/, accessed

11 June 2015.

11. GlobalData, CountryFocus: Healthcare,

Regulatory and Reimbursement

Landscape—France, January 2015.

12. HIS, French government to save

US$383 million over three years by

boosting generic drugs uptake, www.

ihs.com/country-industry-forecasting.

html?ID=1065998895, accessed

22 June 2015.

13. Generics and Biosimilars Initiative,

“France to allow biosimilars sub-

stitution,” http://gabionline.net/

Policies-Legislation/France-to-allow-

biosimilars-substitution, accessed 11

June 2015.

14. Numerof & Associates, Economic and

Clinical Value: Key Drivers For New

Product Development Strategy, http://

nai-consulting.com/economic-and-clin-

ical-value-key-drivers-for-new-product-

development-strategy/, accessed 11

June 2015.

15. Numerof & Asssociates, Patients

as Partners? The Role for “Patient

Centricity” in the New Healthcare

Landscape, eyeforpharma October 2014.

16. J. Sackman and M. Kuchenreuther,

Pharm Technol. 39 (1) 26–30 (2015).

17. C. Ducruet, Médicaments: quand les la

boratoires sont rémunérés à la perform-

ance. Les Echos 3 March 2015. PTE



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12 Pharmaceutical Technology Europe JULY 2015 PharmTech .com

Sean Milmo

is a freelance writer based in Essex,

UK, [email protected].

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The European Medicines Agency is approving a growing

number of advanced therapy medicinal products (ATMP)

despite claims that their commercialization is being hampered

by increasingly complex regulatory and standards requirements.

The creation of ATMPs by a 2007 European Union regulation (1),

backed by a specialist committee for advanced therapies (CAT)

within EMA, aimed to boost development of medicines derived

from progress in cellular and molecular biology.

ATMP development

Initially, the regulation seemed to have little impact on the

number of advanced medicines on the market after the start

of its implementation in early 2009. By mid-2013, there were

only four marketing authorizations from 10 applications in the

three ATMP categories of gene therapy, somatic cell therapy,

and tissue engineering (2).

Over the past few years, however, there have been signs

of a surge in ATMP development. The number of medicine

applications recommended by CAT to be classified as

advanced therapies rose by 26% in 2014 (3). In late 2014, EMA

recommended for EU approval the first advanced therapy

medicine containing stem cells. It is also the first drug for the

treatment of moderate to severe limbal stem cell deficiency

(LSCD), a rare eye condition due to physical or chemical burns

to the eyes that can result in blindness.

Complex regulations

At the same time, the quality, safety, and efficacy rules under

existing and proposed EMA guidelines on ATMPs have been

becoming more complex. One reason is that expanding

knowledge about the new therapies has raised new concerns,

particularly relating to issues regarding the quality of starting

materials and drug substances. The regulators have gradually

become more aware of the biological variability and intricacy

of ATMPs. This tightening of standards seems to be deterring

big pharmaceutical companies rather than small- and

medium-sized enterprises (SMEs) from developing advanced

therapy products.

In a 2014 report (2) on the application of the 2007

regulation, the European Commission, the Brussels-based

EU executive, found that the majority of ATMP research was

being done by small companies and entities. Approximately

70% of sponsors of ATMP clinical trials were SMEs or not-for-

profit organizations, while large pharmaceutical companies

accounted for less than 2%.

The report concluded that because there are “still many

unknowns” with advanced therapies, “it is important to put in

place adequate controls to prevent detrimental consequences

for public health” (2). Nonetheless, it is also acknowledged

that “too burdensome requirements” could have adverse

consequences for public health because they could prevent

the marketing of valid treatments for unmet medical needs.

Data requirements

One onerous requirement is the amount of data needed on

starting materials, such as the source and history of cells,

and their detailed characterization. In addition, a complete

description, including source, characteristics, and testing

details, of all materials used during the manufacture of

products is needed. Some developers of ATMP products

complain about the regulators making demands for data that

existing analytical technologies cannot yet provide. There

have also been complaints about EMA wanting unnecessary

high levels of purity in cell-therapy treatments, especially

those comprising mixtures of undifferentiated cells.

Another matter of contention has been EMA’s insistence

that marketing authorization applicants for tissue-engineered

products must demonstrate through pharmacokinetics the

longevity or persistence of their medicines. “From the point

of view of our members, pharmacokinetics does not include

longevity, but resorption, distribution, and excretion of a drug,”

Matthias Wilken, head of European drug regulatory affairs

at the German Pharmaceutical Industry Association (BPI),

told Pharmaceutical Technology Europe. “The requirement

to demonstrate longevity might lead to extensive clinical

studies that would be an undue burden to pharmaceutical

entrepreneurs,” he explained.

Also in some cases with ATMPs, the regulators are seen

as taking too much of a “generic” approach to advanced

technologies and not making a strong enough distinction with

conventional pharmaceuticals. “The assessors and members

of EMA scientific committees often come from the field of

conventional medicinal products,” said Wilken. “Initially, there

was a lack of understanding of the peculiarities of ATMPs. But

this [understanding] is getting better, as is shown, for example,

Over the past few years, there have been signs

of a surge in ATMP development.

Unravelling the Complexity of EU’s ATMP Regulatory FrameworkThe European Union has a challenging task ahead as it strives to

harmonize regulations on advanced therapy medicinal products.


14 Pharmaceutical Technology Europe JULY 2015 PharmTech .com

by the fact that EMA, along with the Commission, is currently

working on tailoring GMP requirements for ATMPs.”

Risk management

The big regulatory differences between ATMPs and chemical-

based pharmaceuticals is the greater emphasis needed with

biological products on quality issues, mainly because with

many of them, there are gaps in knowledge about ways of

managing their risks. However, EMA has acknowledged the

limitations of applying uniform rules to ATMPs by adopting a

risk-based approach that allows the products to be assessed

on a case-by-case basis.

The distinct approach needed for ATMPs has been highlighted

by the latest EMA guidance (4) on advanced therapies, which

covers the quality, preclinical, and clinical aspects of gene

therapy. The draft guideline (4) on gene therapy was issued in

May 2015 for a period of public consultation ending in August.

It replaces a guidance note (5) published in the early phase of

gene-therapy development in 2001.

Since the 2007 ATMP regulation was implemented, EMA

has had to deal with three applications for gene-therapy

authorizations, only one of which has so far been successful.

“[From a quality perspective], there were no major changes

or inconsistencies in the 2001 guideline that required

an immediate revision,” an EMA spokesman informed

Pharmaceutical Technology Europe. “However, some updates

were necessary, for example, to reflect novel methodologies

for testing and characterization, and also to ensure cross

references to new legislation and guidelines that were

developed separately.”

Quality and safety

Also, the format of the sections on quality and manufacturing

aspects in the revised guideline has been changed to follow

that in the harmonized Common Technical Document (CTD)

for marketing authorization application dossiers, according to

EMA. “This is expected to be helpful for the small developers of

gene-therapy products when compiling their dossiers,” said the

EMA spokesman. As a result, 40% of the 42-page draft guideline

covers quality matters, 30% non-clinical issues, many of which

relate to assessing risks linked to quality management, and only

10–15% to clinical development.

A lot of the obligations in the guideline requirements relate to

the quality of the components in the vectors or delivery systems

of the products. Details of the quality of all starting materials and

their sources have to be provided, including virus seed as well as

mammalian and bacterial cell banks. All raw materials used during

manufacture have to be tested and characterized.

Hospital-based research

Partly due to the detailed EU quality and safety requirements

for advanced therapies, companies developing ATMPs are

critical of an exemption to EU rules granted to hospitals

involved in R&D and the manufacture of the products.

Hospital-based research and production in the sector are

increasing rather than contracting in Europe. This trend is

mainly because some EU states are using these hospitals as

ATMS development centres at the core of national

regenerative medicine programmes.

The United Kingdom, which is seeking global leadership in

the sector, has, for example, a network of cell-therapy centres

of excellence based in leading hospitals. “The establishment

[of these centres] is essential if we are to build a concentrated

critical mass of knowledge, skills, and therapeutic know-how,”

according to a UK government-commissioned report on

regenerative medicine (6).

Under the 2007 EU regulation on ATMPs, member states are

allowed to give hospitals exemption from the legislation as

long as the hospital’s advanced therapies are being provided

on a “non-routine basis” to its own individual patients. Some

organizations are calling for the “non-routine” provision, which

is open to different interpretations, to be extended to cover

products only when a fully validated, EU-approved advanced

therapy alternative cannot be used.

“While the hospital exemption rule allows the early

development and delivery of ATMPs that meet an otherwise

unmet clinical need in a patient, the exemption should only

be used to deliver a product if there is no licensed alternative,

with proven efficacy and safety, available,” says Michael

Werner, executive director of the US-based Alliance for

Regenerative Medicines, a global advocacy group representing

stakeholders in the ATMP sector.

Its European arm has been among the leading critics of

criteria applied for the exemption, particularly those relating

to manufacturing standards. Sceptics about the potential

of exempted hospital-based development systems contend

that they encourage the avoidance of the strict EU data

requirements because the hospitals have to adhere only

to national quality and safety standards, although these

standards should be consistent with those at the EU level.

Even the European Commission in its report (3) on the

impact of the ATMP regulations concedes that the exemption

can enable hospital-based centres to have lower development

costs than commercial ATMP organizations because of the

advantages of being subject to less rigorous standards. A

major objective behind the EU’s ATMP regulation was the

introduction of harmonized standards across Europe. The way

the hospital exemption is operating shows that there is still

some distance to go before full harmonization is achieved.

References 1. EC 1394/2007 Regulation on advanced therapy medicinal

products (Brussels, November 2007). 2. European Commission, Report in accordance with Article 25

of EC 1394/2007 on advanced therapy medicinal products (Brussels, March 2014).

3. EMA, Annual Report 2014 (London, April 2015). 4. EMA, Guideline on the quality, non-clinical and clinical aspects

of gene therapy medicinal products–draft (London, March 2015). 5. EMEA, Note for guidance on the quality, preclinical and

clinical aspects of gene therapy medicinal products (London, April 2001).

6. UK Department of Health, “Building on our own potential: a UK pathway for regenerative medicine,” Report of Regenerative Medicine Expert Group, 24 March 2015 (London). PTE


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The United States Food and Drug Administration programme

to expedite the development and approval of innovativeTTdrugs for serious and life-threatening conditions is a great

success, but the abbreviated development timeframe involved

raises numerous difficulties for manufacturers seeking to ensure

product quality and timely supply. Expert review teams in the

Centre for Drug Evaluation and Research (CDER) and the Centre

for Biologics Evaluation and Research (CBER) are meeting

deadlines and goals for assessing breakthrough designation

requests and for expediting reviews of these drugs, but the

process is resource intensive and has raised questions about

how FDA can keep up with a growing number of candidates.

When the breakthrough programme was established as part

of the FDA Safety and Innovation Act of 2012, stakeholders

envisioned about two to three designations a year. By the end

of May 2015, FDA had received 308 requests for breakthrough

status and had granted the designation for 90, approximately 30%.

Nearly 15 important new therapies have come to market more

quickly as a result, contributing to the recent rise in new drug

approvals. FDA acting commissioner Stephen Ostroff pointed out

at the annual meeting of the Food & Drug Law Institute (FDLI) in

April 2015 that two-thirds of 2014’s near-record 51 new molecular

entities (NMEs) took advantage of at least one expedited review

programme, and many were first-in-class therapies.

Achieving fast approval of a breakthrough therapy creates

challenges for manufacturers looking to develop CMC data

in roughly half the time, noted Brian Kelley, vice-president

for bioprocess development at Genentech. The process, he

explained at the April 2015 CMC workshop sponsored by the

Drug Information Association (DIA), is resource intensive, and

accelerated timelines necessitate new approaches to product

and process development to ensure a reliable supply of a quality

product at launch. The breakthrough designation “does not

mean that sponsors can do less,” he said; they just “need to start

sooner.” This may involve front-loading of crucial product and

process characterization activities, and reaching agreement with

FDA on which actions for optimizing process and methods can

wait until after launch.

High priority for FDA

Expedited quality assessments raise difficulties for FDA as well.

New drug applications (NDAs) for breakthrough therapies often

contain less manufacturing information than usual, requiring

innovative risk-mitigation strategies to ensure product safety.

Agency reviewers are agreeing to less stability data at

submission, accepting amendments during the review cycle, and

increasing postmarketing commitments to cover residual risk,

explained Dorota Matecka, acting branch chief in the Office of

New Drug Products in CDER’s Office of Pharmaceutical Quality

(OPQ), at the DIA workshop and again at the ISPE/FDA/PQRI

Quality Manufacturing Conference in June 2015. Matecka noted

that CDER will schedule CMC-specific meetings during

development to advise on these issues, often including CDER

upper management and subject matter experts.

Robert Wittoft, pharmacist in OPQ’s Office of Process and

Facilities (OPF), similarly urged early discussion of residual

product quality risks. Manufacturers need to decide dosage

form and methods validation strategies much sooner, he said at

the CMC workshop, and should “plan for the unexpected,” such

as facility qualification failures and changes in manufacturing

schedules. Effective communication with contract manufacturers

is crucial, as is a transparent presentation in the application of

design evolution and a rationale for commercial manufacturing

process and controls.

John Groskoph, senior director at Pfizer, observed that for most

breakthrough therapies, market applications are being filed with

FDA after Phase II studies, approximately two years ahead of a

traditional NDA that is based on Phase III data. The time reduction

presents “significant challenges to the development team,” he

commented, and may be further complicated if the firm seeks

to file simultaneous applications in Europe, Japan, and emerging

markets, as well as in the United States.

Japan, for example, has established the SAKIGAKE designation

programme for innovative medicines and medical devices that

are developed first in Japan and offer “radical improvement”

over existing therapies to treat critical diseases, explained

Yoshihiro Matsuda of Japan’s Pharmaceuticals and Medical

Devices Agency (PMDA), at the CMC workshop. He described a

greatly accelerated development and approval process for such

therapies, combined with stronger postmarketing oversight. The

initiative, he noted, requires risk-based assessment strategies

and a product quality lifecycle management plan, combined with

clear analysis of what can be evaluated during review, and what

can be analyzed later after approval.

Groskoph noted that successful launch of a breakthrough

drug involves addressing numerous issues: data availability,

meaningful and practical specifications, robust manufacturing

processes, clinical or commercial site production, site readiness

for pre-approval inspection, deferral of Phase III studies to post

approval, and the need for comparability protocols to facilitate

postapproval changes. Communication with FDA is important

throughout the breakthrough development process, he added,

to facilitate agreement on strategies for dealing with unexpected

production problems.

Breakthrough Drugs Raise

Development and Production ChallengesManufacturers and the US FDA look for innovative strategies to meet accelerated timeframes.

Jill Wechsler is Pharmaceutical Technology Europe’s

Washington editor, tel. +1.301.656.4634,

[email protected].


For biologics, breakthrough designation may prompt greater

focus on the reliability of the Phase I cell line, process and

formulation, as shorter pivotal trials may truncate optimization

of the Phase III process, added Kelley. A key decision for

manufacturers is whether to devote more resources to the

project early to front-load process characterization and validation

activities, even before gaining the breakthrough designation.

Such an approach may involve testing lots before assay validation

is completed; filing with broader specifications with the aim of

tightening them post-launch; launching from the clinical site

and transferring to commercial post-launch; and including a

postapproval lifecycle management plan in the application to

support deferral of certain activities. But, Kelley commented,

“you can’t place bets” on potential breakthroughs too frequently

without overly straining company resources.

Sustainable programme?

The growth in breakthrough designation requests is prompting

FDA and stakeholders to examine options for refining breakthrough

criteria so that FDA will be able to manage the programme. The

agency is examining past designation decisions and why it turned

down certain requests to see if the bar is too low; a goal is to

better educate manufacturers on which promising experimental

products really qualify for breakthrough status.

FDA “can’t sustain a programme where everything is a

breakthrough,” commented John Jenkins, director of CDER’s

Office of New Drugs, at an April 2015 workshop on breakthrough

therapy designation criteria organized by the Brookings Institution.

FDA officials explained that extensive resources are involved in

determining designations and in supporting development and

accelerated review of breakthrough candidates. Manufacturers

acknowledged that designation denials could decrease if sponsors

sought breakthrough status only for therapies that offer truly

substantial improvements in patient care. And they indicated that

additional resources from industry are warranted to support the

unexpectedly large breakthrough programme.

While FDA can quickly approve products with clear

outstanding value, Jenkins noted that such efforts may be

stymied by manufacturing problems and inspection delays.

There are situations where the clinical data are good, but

where sponsors “have to get manufacturing and facilities in

line,” he said. Sites for inspections need to be identified early,

Jenkins advised, especially for overseas facilities that may raise

travel difficulties. Kay Holcombe, senior vice-president of the

Biotechnology Industry Organization, urged close examination

of ways to prevent approval delays due to difficulties in making

a drug according to specifications. “If this is a hurdle at the

end,” she said, “we need to deal with it more effectively.” PTE

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OUTSOURCING REVIEW

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Jim Miller is president of

PharmSource Information

Services, Inc., and publisher

of Bio/Pharmaceutical

Outsourcing Report,

tel. +1.703.383.4903,

Twitter@JimPharmSource,

[email protected],

www.pharmsource.com.

These are high times for contract development

and manufacturing organizations (CDMOs) and

contract research organizations (CROs). A record

flood of external financing is flowing into the bio/

pharmaceutical industry. Global bio/pharmaceutical

companies are outsourcing more of their development

activity, and the United States Food and Drug

Adminstration is being especially accommodating.

R&D spending is growing, and the clinical development

pipeline is really coming to life.

The explosion of development activity is pushing

the contract services industry capacity to its limits,

particularly for early development. Providers of

preclinical research services, such as Charles River

Laboratories and Covance, are rushing to reactivate

capacity that was mothballed following the financial

crisis. CDMOs that were fighting for survival two years

ago are now telling clients there is a three- to six-

month wait for a production slot.

To expand or not to expandDespite the strong market environment, the decision

to expand capacity is not an easy one for CDMO

executives, who were burned twice in the past decade.

After a period of robust activity in the late 1990s,

funding and development activity declined sharply in

the early 2000s as a result of the dotcom bust and

some major clinical failures. Then just as things were

recovering in mid-decade, the global financial crisis

once again cut the product development pipeline to a

trickle.

New manufacturing and analytical capacity

can take a year or more to construct, equip, and

validate, and in that time, an upset in industry or

macroeconomic conditions can leave CDMOs with a

lot of unused capacity that still has to be paid for. So it

is not surprising that CDMO executives are careful in

committing to new capacity.

Executives’ concerns are warranted because the

surge in funding that is propelling demand is driven by

the skyrocketing valuations of biopharma companies.

Valuations of publicly-traded bio/pharma companies (as

measured by the Nasdaq Biotech Index) have climbed

300% since 2010, three times faster than the broader

stock market (as measured by the S&P 500). Thanks to

that surge in equity prices, nearly 60% of the increased

external funding flowing into early stage bio/pharma

companies has come from initial public offerings (IPOs)

and secondary offerings by companies that are already

public (see Figure 1). But the rapid run-up in bio/pharma

stock prices has given rise to increased concern about

whether the “biotech bubble” is about to pop.

CDMOs Cautiously Address ExpansionWhile all market signs are pointing up, memories of

past setbacks may discourage CDMOs from expanding capacity.

OUTSOURCING REVIEW

Figure 1: External financing for early-stage bio/pharmaceutical companies.

$-

$5.0

$10.0

$15.0

$20.0

$25.0

$30.0

$35.0

2008 2009-12 2013/14

Upfront license fees

Venture capital

Secondary offering

IPO

Private equity

Other



Outsourcing Review

Funding stabilityPharmSource has been looking closely

at the funding issue, and while the

possibility of the biopharma bubble

bursting is a concern, a disruption in

industry funding activity is not likely

to be as damaging today as it was

in 2008. This optimism is based on

several key observations:

Global bio/pharma companies

increasingly depend on early-

stage companies to feed their own

pipelines, so they have a strong

interest in supporting them. Partnered

or acquired products account for

50% or more of approvals received

by global bio/pharma companies in

recent years, while upfront payments

from partnering deals with global

biopharma companies provided

20% of the total funding received by

early-stage companies. Investment

in partner relationships, including

licensing, may exceed 30% of total

R&D spending at the global bio/

pharmaceutical companies.

Venture capital is not nearly as

volatile as public financing. Venture

capital funding for bio/pharma

companies stayed fairly consistent

through the financial crisis and has

risen only gradually in the past several

years. Global bio/pharma licensing

activity will continue to provide an exit

for venture capital investors even if

public equity markets shrink.

The early-stage companies have

plenty of cash. PharmSource analysis

indicates that 70% of the public

biopharma companies have more than

two year’s cash on hand, assuming

current levels of spending.

CDMOs, therefore, can expand

with the confidence that demand for

their services should remain robust

for the foreseeable future. Capital for

expansion should be readily available

given market conditions and a growing

willingness on the part of bankers

to lend, but the biggest challenge

for CDMOs will be getting enough

technical and project management

staff to meet the growing demand.

CDMOs and contract labs are already

hiring aggressively, and poaching

of staff, fed by rising salaries, has

become a big problem. This poaching

is especially true for people with the

higher-order technical skills needed

for prime growth segments such as

advanced formulations and analytical

services for biopharmaceuticals.

Restrained growth of capacity may

not be the worst thing for CDMOs,

however. Tight capacity conditions

are likely to help CDMOs improve their

profitability, just like they have for the

airlines. After years of being beaten

up on price by clients, especially

the global biopharma companies,

CDMOs and contract labs finally

find themselves with some pricing

power and the ability to improve their

bottom lines. A healthy and profitable

CDMO sector is in the best interest

of the bio/pharmaceutical industry

The explosion of development activity is pushing the contract services industry capacity to its limits.

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Poor solubility is an ongoing challenge in

pharmaceutical development. A drug must be in

solution form for it to be absorbed regardless of the

route of administration. The solubility of an API,

therefore, plays a crucial role in bioavailability given

that drug absorption is a function of solubility and

permeability.

Modern drug discovery techniques, with advances

in combinatorial chemistry and high throughput

screening, continue to fill drug-development pipelines

with a high number of poorly soluble new chemical

entities (NCEs). “Estimates have varied over the

years, but it is reported that 40%–70% of NCEs are

poorly water-soluble,” observes Sampada Upadhye,

PhD, technology platform leader for bioavailability

enhancement & OptiMelt, Catalent Pharma Solutions.

“There has been a tremendous amount of research

going on in the industry to overcome the challenges

in bringing poorly soluble drugs to the market.”

Improving success rates in drug development Selecting a suitable drug-delivery approach for

these challenging NCEs depends on various

parameters, explains Praveen Raheja, associate

director, Formulations, at Dr Reddy’s CPS,

“for example, the drug solubility, chemical

composition, melting point, absorption site, physical

characteristics, pharmacokinetic behaviour, dose,

route of administration, and intended therapeutic

concentration, to name a few.” An analysis of all

these parameters is required to determine the most

appropriate method of drug delivery, he says.

According to Marshall Crew, PhD, vice-president,

Global PDS Scientific Excellence, Patheon, there

are two aspects that must be understood in a

comprehensive way before proceeding toward the

best solubilization technology—the drug molecule

and the target product profile. “The dosage form,

dosage, and other requirements for the drug product

must be taken into consideration, along with the

molecular properties and profile of the API,” he

says. “Modern pre-formulation approaches begin by

understanding the target product attribute space,

and leverage modelling to more fully characterize

and understand the molecule.” Crew explains that

this approach enables solubilization formulation

scientists to know the starting point and direction

Solving Poor Solubility to Unlock a Drug’s Potential

Modern methods and modelling offer a better way to understand

solubility issues and solve today’s complex formulation challenges.

Adeline Siew, PhD



Solubility Challenges

of the process from the earliest

stage to formulation design and

optimization.

“Once the drug product

requirements have been understood

and the API characterized,

solubilization technologies can be

screened to identify the best fit

for the particular drug and desired

outcome,” Crew adds. After the

technology has been identified, the

next step is to conduct experiments

involving a range of excipient/

polymer models in combination with

the drug. Crew advocates the use

of computational screening, which

allows a greater number of options to

be explored more efficiently, thereby

increasing the likelihood of identifying

the best approach.

Dan Dobry, vice-president, Bend

Research, a division of Capsugel

Dosage Form Solutions, also

recommends a mechanistic, model-

based approach. “Simple modelling

and characterization tools can relate

physicochemical aspects of the

compound and therapy to potential

delivery challenges,” he notes. “The

models are often not quantitative in

early development, but give context

to experiments, in vitro and in vivo, to

help shape the problem statement and

pair the right delivery technology.”

Mastering multiple delivery

technologies, from formulation

through to scale-up and

manufacturing, reduces bias for a

particular technology, says Dobry,

and allows each technology’s sweet

spot to be exploited, rather than

trying to force fit a technology to a

problem statement. He further adds

that integrating appropriate enabling

technologies into lead selection

(instead of using them in a rescue

mission during mid-development,

when it may already be too late),

can streamline the process and

help identify the most effective

combination of molecule and drug-

delivery technology.

Dieter Lubda, PhD, director,

Process Chemical Solutions R&D

Franchise Formulation, Merck

Millipore, finds that conventional

solubilization approaches such

as physical modifications of APIs,

micronization, or nano-milling tend to

have limited results. “The formulation

of new drugs often needs new

technologies and excipients that

can induce specific solubility- and

bioavailability-enhancing properties,”

he says. However, Lubda stresses that

the interaction of new technologies

and the excipients used is a far

more complex scenario. Instead

of focusing on one technique, it is

important to consider how a range of

excipients or approaches could work

best for the poorly soluble API under

development. “This helps increase

the success rate of selecting suitable

drug-delivery solutions,” he asserts.

Tackling solubility challengesWhen considering solubility, Dobry

says the industry has a range of

commercial solutions to choose from,

such as size reduction, and the use

of lipids or amorphous dispersions.

These proven approaches can be

selected based on the individual

drug’s properties and specific

problem statement.

Each method, however, has

its limitations and may pose new

formulation challenges, notes Upadhye.

Strategies such as polymorphism,

salt formation, co-crystal formation,

and the addition of excipients may

marginally increase drug solubility, but

often have limited success in increasing

bioavailability, according to her. In

some cases, they can even increase

drug toxicity, resulting in negative side

effects, she says.

Although particle size reduction

may be a safe way to increase drug

solubility, it does not alter the solid-

state properties of the drug particles,

Upadhye observes. In addition,

solid dispersions, solid solutions,

amorphous generation, and lipid-

based formulations each has its own

set of challenges that can affect drug

stability and drug loading capacity,

she adds.

One of the greatest formulation

challenges today, according to

Dobry, is the fact that poorly soluble

compounds often present other

problems, such as metabolism or

permeability challenges, drug-to-

drug interactions in a combination

dosage form, or the need to modify

pharmacokinetics (e.g., blunting the

maximum concentration [Cmax]

or extending drug release). “These

challenges rapidly increase as the

dose increases and desire for dosage

form burden comes down,” Dobry

notes.

According to Stephen Tindal,

director, Scientific Affairs, Softgel

R&D, Catalent Pharma Solutions, dose

is the number one problem. “Unless

you can get significant increases in

bioavailability, the patient has to take

multiple large unit doses whether

they’re tablets, capsules, or softgels,”

states Tindal. Another problem is

because APIs are not designed with

enabling technologies in mind, there

can be a suboptimal fit between the

API and the dosage form.

“It can be beneficial to not fix the

salt form or the polymorph form too

early,” says Tindal. “For example, if

the API salt form has been selected

with water solubility in mind, this may

not be the ideal form for presentation

as a lipid based drug delivery system.”

Lubda explains that the first

key consideration in formulation

development is the route of

administration. “The main question

here is where the API needs to go

in the body and how the drug can

best be formulated to reach this

targeted location,” he continues. “In

this challenge, the prerequisite for

API bioavailability is to increase its

solubility and permeability. These

parameters must be optimized to

achieve optimal release properties

and the desired plasma profile within

the required therapeutic window.”

“Depending on the properties of

the API, we have to assess if the drug

can be formulated with standard

formulation technologies or whether

we need to explore non-conventional

approaches,” Lubda expands further.

“Developing a good formulation is

not easy per se. The excipients used

could interfere with the drug during

the formulation process (e.g., a pH

shift during wet granulation) and

result in a lower therapeutic effect.”

Developing an oral formulation According to Raheja and Lubda, the

main challenges encountered during

the development of oral formulations

for poorly soluble drugs are:

• ensuring the stability of the

formulation during processing and

in the gastrointestinal (GI) tract

(e.g., avoiding precipitation of the

drug in gastric fluids)




• achieving consistent drug release

rates

• considering food effects, such as

different levels of drug absorption

during fed or fasted states

• taking into account the presence

of p-glycoprotein and cytochrome

P450 (CYP) enzymes.

A common problem, as Raheja

highlights, is determining the

combination of suitable excipients

and the enabling technology that

increases solubility, as well as

determining the appropriate tool to

predict the solubility in-vivo so that an

in-vitro in-vivo correlation (IVIVC) can

be established.

Lubda emphasizes the importance

of choosing the best excipients for

the formulation, adding that process

conditions such as heat or moisture

during drug development are also

crucial. “In the end, it comes down to:

How can we cost-effectively formulate

APIs with good content uniformity?”

he asserts and highlights some key

questions that should considered:

• Can we simplify complex

formulations (requiring large number

of excipients) that can lead to

unexpected excipients interactions

and limited drug stability?

• How can we influence the

recrystallization of amorphous APIs

and what are the pH effects on

their stability?

Lubda sums up that the

ultimate goal is to achieve a robust

manufacturing process that takes into

account disintegration and dissolution

of the oral dosage form, hardness,

content uniformity, waste, and

productivity with high tableting speed.

According to Crew, developing a

customized formulation for poorly

soluble drugs requires achieving the

best balance of dose, polymer, and

API loading to allow the final drug

product to have the required stability,

manufacturability, and performance.

“To accomplish this type of local

optimization within a global context,

using a modern approach is essential,”

he notes. Crew recommends a

systematic methodology, employing

rigorous scientific practices, and

then performing extensive in-silico

simulations. “Fortunately, the

computational intensity of this type

of exploration and analysis is now

feasible,” he adds.

Choosing a suitable solubilization strategyWhen selecting a solubilization

strategy, a number of considerations,

such as the physicochemical and

physiological properties of the drug,

should be taken into account. Lubda

lists the following key factors to

consider:

• dosage form

• administration route

• mode of action (e.g., oral local or

oral systemic for fungal drugs)

• API dose per unit or API load

• physicochemical properties of the

API (i.e., pH-dependent solubility,

pKa value(s), log P, temperature

sensitivity, shear sensitivity,

solubility in suitable solvents,

known undesirable interactions

with excipients, polymorphs,

properties of crystalline state vs

amorphous state)

• suitability of the manufacturing

process for the API

• scalability of the formulation

process

• differences in performance during

feasibility studies and screenings

• availability of necessary equipment

for process and method used

• stability of the final formulation and

shelf life

• total cost of ownership

• intellectual property and licensing

considerations.

Raheja offers a real-world example.

“If a compound has an acidic or

basic functional group and the log

P is between 1.0 to 3.0, one could

explore buffer systems to solubilize

it,” he says. However, he notes some

possible drawbacks—a buffer-based

system could result in precipitation in

the GI. In such cases, anti-nucleating

polymers could be used to overcome

this problem. “These agents maintain

a high degree of supersaturation

and help improve bioavailability,”

Raheja explains. “Other solubilization

techniques such as complexation

and solid dispersions can also be

considered for compounds with

a log P in the range of 1.0 to 3.0.

For compounds with a log P of 5,

it is better to explore lipid-based

systems.”

Each solubilization technique has

its pros and cons, Upadhye observes,

and only a careful consideration of the

API’s physical, chemical, and thermal

properties as well as its mechanical

properties, will allow the best

solubilization technique to be selected.

While most experts would

agree on the list of key factors

guiding a solubilization strategy,

Dobry stresses the importance

of having a framework or model

that puts method selection into a

broader context that also considers

the mechanism of dissolution

and absorption, and allows for

problem statement definition, risk

assessment, and sensitivity analysis.

“In this context, it is important to

have basic pharmacokinetic data

of the crystalline drug in animal

models to guide initial model

development,” he continues. “We

find this aspect to be so important

that we have developed discovery

stage formulation tools to generate

pharmacokinetic/pharmacodynamic

data in animals, even for poorly-

soluble actives.”

While the drug molecule plays the

key role in the decision, Crew adds

that other crucial considerations

include the amount of API available at

the earliest stage of development and

the drug product’s goals. “In some

instances, the initial assessment and

process development can employ

one technology, and then, when

the formulation design has been

completed, another technology

can come into play,” he says. Crew

provides an example: creating an

amorphous solid dispersion, for

which either spray drying or hot-

melt extrusion (HME) might be used.

In this case, the API dictates the

options available, he explains, and the

decision tree includes such factors as:

• the amount of API

• chemical properties

• log P

• melting point

• solubility of API in solvent or

polymer

• size of molecule.

These are only some of the factors,

but they can only be derived from

a thorough characterization of the

molecule, Crew points out. Because

the amount of API required for

early formulation using spray drying

is significantly less than what is

required for HME, an early feasibility

study might be done using that

technology, if the API lends itself to



Addressing Formulation Needs With A Different Technology:

Say “Hello” to Ion Exchange Resins

ON-DEMAND WEBCAST originally aired Wednesday, June 24, 2015

Register for free at www.pharmtech.com/pt/ion

Event Overview:

Ion exchange resins have long been in the formulator’s toolkit, but only recently has there been an increased

interest in their use as excipients. Amie Gehris, technical service manager for Dow Pharma Solutions, will

discuss the value and benef ts ion exchange resins bring to drug formulation challenges such as taste masking,

abuse deterrence, controlled release, and more.

Key Learning Objectives:

Attendees will learn about:

t� The chemistry and history of pharmaceutical ion exchange resins

t� Processing and use of ion exchange resins

t� Ion exchange resins drug delivery applications and case studies

Who Should Attend:

t� Pharmaceutical formulators

t� Pharmaceutical R&D scientists

t� R&D and formulation managers

t� Process and materials engineers and manufacturing experts

For questions contact

Sara Barschdorf at [email protected]

Presenters:

Amie Gehris

Technical Service Manager

The Dow Chemical Company

True L. Rogers R.Ph., Ph.D

Technologies Leader

The Dow Chemical Company

Moderator:

Rita Peters

Editorial Director

PT

Presented by PT Sponsored by Dow

® Trademark of The Dow Chemical Company.

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HME (i.e., if its melting point does not

exceed 200 °C–225 °C).”

Weighing up the different solubility-enhancement approaches“Several technologies are available

to overcome solubility challenges,”

states Lubda. “One approach is to

influence the surface area of the

API particles using micronization,

nanonization, co-grinding, or

precipitation from supercritical

fluids. The other alternative is

to increase the solubility with

solubilizers (polymers, surfactants,

or cyclodextrins), lipid-based

formulations (e.g., self-emulsifying

or self-micro-emulsifying drug

delivery systems [SEDDS/SMEDDS]),

polymorphs, salt formation, or

co-crystals.” He notes that some

newer solubilization techniques

attempt to address both the

surface area and solubility through

the formation of liquid and solid

dispersions or porous inorganic

carriers such as mesoporous silica.

“The overall goal is to improve

API solubility and achieve a higher

dissolution rate, which facilitates

faster drug absorption,” he says.

According to Lubda, micronization

of API is challenging, especially at

production scale. “Batch-to-batch

homogeneity is poor,” he observes,

further highlighting the potential

stability problems that could occur

due to the high energy input, apart

from the difficulty in achieving

content uniformity in the solid-

dosage form. “Surfactants can be

seen as a straightforward approach

to influence API solubility,” he adds.

“But because they are not inert

excipients, surfactants can interact

with APIs and other excipients.

Their effects are hard to predict

and surfactants potentially have an

influence on biological membranes

as well as possible side effects.”

Lubda views porous inorganic

carriers (e.g., silica) as well as liquid

and solid dispersions as promising

technologies to solve solubility

challenges.

Poor solubility is clearly a problem

that will continue to challenge drug

developers. As Crew points out,

the number of insoluble molecules

continues to rise. “During the

decade of the 1970s, only 0.6% of

FDA-approved molecules had been

solubilized,” Crew observes. “The

next two decades showed increases,

and by the 2000s, this category

accounted for more than 10% of

approved drugs.”

According to Crew, Patheon

analyzed the number of drugs

approved by FDA between 1970

and 2013, which used diverse

solubilization platforms (including

lipids, amorphous solid dispersions,

nanocrystals, and other alternative

technologies). While lipid systems

were the most widely used in

the 1980s, and continue to be

favored today, Crew says that solid

dispersions saw a steep increase

in the mid-2000s, and continue on

a rapid growth rate even today.

Findings from Patheon’s study show

that lipids dominated with a 50%

share, solid dispersions took second

place with 30%, ahead of the next

closest technologies at less than

10%. Catalent’s softgel expert Tindal

concurs that lipid-based formulations

have a historic advantage over solid

dispersions, but notes that use of

solid dispersions is increasing.

Solid dispersions continue to show broad applicabilitySolid dispersions are widely used

as a solubilization technique. Kevin

O’Donnell, PhD, and William Porter III,

PhD, who are both associate research

scientists at Dow Pharma & Food

Solutions, attribute it to the ability

of solid dispersions to drastically

improve the solubility of most APIs.

“While solid dispersions present their

own challenges, they eliminate the

issues associated with traditional

techniques,” O’Donnell observes.

“Non-ionizable APIs or those that do

not fit in complexing agents can now

find success.”

“Owing to its simplicity from

both manufacturing and process

scalability standpoints, solid

dispersion has become one of

the most active and promising

research areas and is therefore of

great interest to pharmaceutical

companies,” comments Upadhye.

“The term ‘solid dispersion’ refers

to solid-state mixtures, prepared

through the dispersion, typically by

solvent evaporation or melt mixing,

of one or more active ingredients

in an inert carrier matrix. In these

dispersions, the drug can be present

in a fully crystalline state (in the

form of coarse drug particles), in

a semi crystalline state, or in fully

amorphous state (in the form of a fine

particle dispersion, or molecularly

distributed within the carrier). Such

systems prove to be very effective

for enhancing the dissolution rate of

low solubility drugs.”

Dobry says that the approach

is broadly applicable because of

its mechanism of stabilization and

dissolution, as well as a scalable,

precedented process. “The most

prominent advantage of solid

dispersions is the purely physical

change of the active compound

(mainly from the crystalline to the

amorphous state). If the change is

performed in a controlled manner

you don’t have to deal with concerns

about undesired effects from

chemical changes of the compound,”

Lubda adds.

According to O’Donnell, until

recently, the number of methods

available to a formulator to generate

an amorphous solid dispersion was

limited. “However, recent growth in

the techniques capable of generating

an amorphous solid dispersion—such

as spray drying, HME, precipitation

methods, co-milling, KinetiSol

dispersing, cryogenic methods, and

others—has created processing

flexibility, allowing almost any API to

be formulated into a solid dispersion,”

he notes.

Spray drying and HME are currently

the most commonly used methods

to produce solid dispersions. “Spray

drying is highly effective at generating

the amorphous form of an API and

can be used for APIs that have low

degradation temperatures,” Porter

observes, adding that selecting the

appropriate polymer and solvent

will ensure the resulting product is

homogenous.

HME, on the other hand, is a

versatile process that does not

require solvent. “Moreover, because it

is a continuous process with narrowly

defined output quality attributes, HME

represents an ideal manufacturing

platform for the implementation of

process analytical technology (PAT),”

Upadhye says.




For amorphous solid dispersions,

a primary challenge is the stability

of the amorphous drug, according to

O’Donnell. “Improperly formulated

systems may recrystallize into

more thermodynamically stable

and less soluble forms, resulting in

dramatic changes in the dissolution,

absorption, and therapeutic effect of

the API,” he points out. “The stability

of crystalline formulations is also

of great concern if a high-energy

polymorph is selected, due to the risk

of polymorphic transformations that

can have negative effects.”

“Another challenge consistently

observed is that many poorly soluble

drugs require delivering a high dose of

the API to the patient,” Porter notes.

“This issue creates complexity in

designing adequately sized dosage

forms and can result in adverse drug

effects and poor patient compliance.”

Porter explains that while amorphous

solid dispersions may reduce the

required dose circumventing this

issue, a high drug load lowers the

amount of stabilizing polymer present

in the formulation, which can result in

the aforementioned stability concerns.

Raheja sees great potential in solid

dispersions citing a growing number

of commercial products and those in

development. “In the past decade, a

lot of understanding on formulation

components, analytical tools, and

scale-up challenges have improved,”

he states. “Our own experience with

this technology has brought products

into different clinical and commercial

stages.”

“While simple solid dispersions

will continue to be a cornerstone

technology for enhanced

bioavailability, we need to continue

to innovate,” says Dobry. “This

will include the evolution and

combination of the best aspects

of multiple technologies, such as

combining manufacturability and

solid-state stability of amorphous

dispersions with rapid dissolution and

permeability enhancement of lipid

formulations.”

Mesoporous silica gains recognition According to Lubda, the use of silica

has been gaining traction since it

was first used as a drug carrier in the

1980s. Most research has focused on

the use of ordered mesoporous silica.

“Materials such as SBA-15 (Santa

Barbara Amorphous-15) or MCM-41

(Mobile Composition of Matter-41)

are pure silicon dioxide particles with

an ordered mesoporous structure

but remain on scientific production

levels. Silica materials with unordered

mesopores are most widely used

because their manufacturing process

is easily scalable and the pore

structures are known to be pressure

resistant,” he elaborates.

These mesoporous silica particles

are inert and have a large internal

surface area (potentially exceeding

1000 m²/g) that provides space for

the drug molecule to be absorbed,

which is crucial for drug loading

capacity, Lubda says. The challenge,

however, will be making this surface

area accessible to the drug molecule.

Different silica carriers can be used

for drug delivery, Lubda explains,

but it is important that they are

monograph-compliant and have

GRAS (generally regarded as safe)

status. The underlying solubilization

technology is to impregnate an

amorphous drug form into the pores,

with the help of an organic solvent in

a pre-formulation step, and to prevent

recrystallization during dissolution in

the body, Lubda says. The result after

drying and removal of the solvent is

an intermediate, in powder form, of

silica with the API. In most cases, he

notes, such intermediates enhance

the solubility (by supersaturation),

dissolution rate, and stability of the

poorly soluble small molecules. “This

solubilization approach is applicable

to a broad range of drugs, as the API

only needs to be soluble in a volatile

organic solvent,” says Lubda, adding

that the final formulation can easily

be compressed into a tablet and the

process is scalable.

Recent advances in the field Given the range of solubilization

technologies available, poor solubility

does not necessarily prevent a drug

from reaching the market anymore,

notes Lubda. Research promises to

expand the range of technologies

available in the future.

“There is an increasing focus on

understanding solubility and more

importantly, the bioavailability

of drugs in general,” Lubda

remarks. Experts notice the

increasing collaboration between

pharmaceutical manufacturers

and academic research groups to

develop more appropriate, better

fitting test systems for in-vitro and

in-vivo studies that will help provide

deeper insights into drug properties

and further the understanding

of solubilization strategies. “The

ability to model both molecules

and excipients separately and then

in combination in silico allows

access to a broader solution space,

and also significantly increases

the predictability of solubilized

outcomes,” Crew adds.

Dobry notes that, during the past

decade, significant advancements

have been made in improving the

stability, bio-performance, and

manufacturability of NCEs that, in the

past, might have been considered

too insoluble to proceed into the

next drug-development phase. “An

important advancement has been

in solid-state characterization and

stability prediction of amorphous

dispersions,” Dobry observes. “Five

to 10 years ago, this was seen as an

Achilles heel. Now, it is one of several

important aspects to address in a

risk assessment, he says. “Continued

innovation will be needed in this

area, as molecules and formulations

become more complex.”

The ability to characterize

dissolution mechanisms has been

a major achievement, Dobry says,

especially since today’s formulation

problems tend to transcend simple

insolubility. “In many cases, there

is a need to incorporate enabling

technology into the discovery

interface,” he explains. Integrating

quality-by-design principles in

development, for example, allows

interaction between the process

and formulation attributes to be

identified, enabling the manufacturing

space to be optimized, while allowing

performance and stability targets to

be met.

As formulations become

increasingly complex, new

approaches tackle the problems

of solubility and bioavailability in

different ways. The future promises

to bring more solutions to what may

once have been viewed as insoluble

problems. PTE



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The regulatory requirement for data integrity is not new and was

stated in United States 21 Code of Federal Regulations (CFR), Part

11 in 1997 (1). In the area of cGMP, regulatory focus on the integrity

of electronic and paper-based data has increased sharply. Systems

that formerly were given only superficial reviews have started

to come under intense scrutiny. Standalone raw data-generating

systems and business processes, as well as interfaced business and

production control systems, present a large pool of crucial business

information with which data integrity issues can occur.

Reviewing regulatory citations concerning data integrity, including US

Food and Drug Administration warning letters and European Medicines

Agency statements of GMP non-compliance, invariably leads to the

conclusion that the current focus of the regulator lies strongly with

systems involved in generation of quality-control data. Numerous early

citations were caused by fraudulent behavior; therefore, focus also has

been on the few tools that can detect such behaviour after the fact.

The primary detection tool is a system’s capability to write a detailed

audit trail subject to the rules of 21 CFR 11. Therefore, some industry

approaches to ensuring data integrity will concentrate on these types

of systems and their respective audit trails.

Two other important aspects of data integrity include the

validated state of a process or a computerized system (ensuring

accuracy of generated or recorded data), and the management of

critical authorizations (protection of data to avoid integrity breaches

during operation).

When implementing measures to establish, maintain, and review

data integrity across an organization, the following steps should

be followed:

• Awareness. It is crucial that employees at all levels understand

the importance of data integrity and the influence that they can

have on the data with the authorizations assigned for their job

roles. This understanding can be achieved with a relatively short,

simple training session across an organization. More detailed

sessions are required for process, system, and data owners; this

training should describe the responsibilities for data within each

employee’s remit, as well as accountability for and consequences

of accidental or intentional integrity breaches.

Kurt In Albon, kurt.

[email protected], is head

of global IT quality, Daniel

Davis, PhD, is a global

GMP compliance specialist,

and James L. Brooks

is a global quality control

systems manager, all with

Lonza Group Ltd.

• Standardization. The

standardization step should be

based on available regulatory

guidance, such as definitions (2)

from the UK’s Medicines &

Healthcare products Regulatory

Agency (MHRA), to ensure a

common understanding of

terms and concepts. This step

should include, but not be limited

to, interpretation of available

government regulations and

guidelines, internal procedures,

terminology and concepts, as well

as levels of risk for data.

• Gap analysis. A subsequent

gap analysis of processes and

systems, with emphasis on the

existing controls for data integrity

and their compliance with

regulations, will yield the basis

for the next step in the process:

the determination of the risk

associated with each process or

system and the data generated

or modified by it. As with any

risk assessment, thresholds for

mitigating action should be set

before assigning criticalities to

the individual data elements and

their controls. In general, any

such risk-based approach should

be based on accepted standards,

such as ICH Q9, Quality Risk

Management (3).

• Risk determination. The

completed risk determination

will provide the basis for

implementation of new required

controls, in addition to existing

ones. GMP-compliant businesses

often will have data integrity

under good control. The

determined level of risk should be

taken into account when deciding

whether to implement technical or

procedural controls.

Once implemented, the systems,

controls, and data should be

reviewed periodically, at a frequency

commensurate with the determined

risk, type of system, and industry

guidance/regulatory requirements.

Table I indicates the difficulties

associated with the different types

of systems.

Audit trailsAccording to agency warning letters,

FDA expects that reviews of audit

trails are done as part of the release

A Risk-Based Approach to Data IntegrityHeightened regulatory scrutiny of data integrity highlights the need for

comprehensive reviews and strategies for managing mission-critical information.



QA/QC: Operational Excellence

of each single batch. Equally, the

notion that reviews of audit trails

from analytical release tests should

be done for each test is widespread.

It is obvious, though, that

indiscriminate application of such

rules will generate a large number of

reviews of perfectly accurate audit

trails, revealing no untoward activity,

and—ultimately—not generating

value, ensuring product quality, or

improving patient safety.

To perform meaningful audit trail

reviews, it is important to ask what

the review aims to accomplish. A

review to determine whether an

audit trail is functioning correctly

should be limited to the initial

validation phase of a computerized

system. Typically, for the systems

listed in Table I, audit trail

functionality is a standard, off-the-

shelf feature, possibly configurable

to define what activities the end user

wants to record in the audit trail.

There is no need to re-qualify the

correct function of an audit trail on a

periodic basis. A proper operational

qualification test will establish valid

functionality, and requalification

should be limited to system tests

after major software upgrades. Of

course, prior to implementation, an

audit trail should demonstrate it is

capable of recording events with

sufficient granularity. If this is not

possible, it will be difficult to perform

meaningful and value-adding reviews

of the recorded information.

Reviewing an audit trail to

establish data integrity requires

prior definition of critical items to be

reviewed. For this definition to be

meaningful, the relationship between

the audit trail elements and the

critical quality attributes (CQA) being

tested by an analytical instrument,

or the critical process parameters

controlled and measurements

recorded by a control system

during manufacturing, should be

established. There should be a strong

relation between the criticality of

test results and the frequency and

depth of review of associated audit

trails. Audit trails for analytical

tests that do not have bearing on

CQAs do not have to be reviewed

to the same degree. To support

this practice, a scientifically sound

definition of the CQAs is required

prior to implementation of the review

cycle. Development of analytical

methods, manufacturing, or business

processes should include the

definition of these critical attributes;

If these attributes are not defined,

it will be difficult to decide at a later

time which data integrity breaches

are critical in terms of patient safety

and which are not.

For a chromatography data

system, for example, analysts will

require some flexibility to work with

the data acquired by the system and

the connected instrument to account

for changes in system performance.

Extensive manipulation, however,

can have the effect that results—

which were outside of specification

during data acquisition—can later be

in specification. For such analytical

tests, critical entries in the audit trail

to be reviewed for high-risk (release)

samples must include manual

integration events or changes to

processing method integration

events. In another example, the

completion of sample well templates

on microtiter plate readers after data

acquisition causes a misordering

of events, which will only appear

in the audit trail. Audit trail entries

indicating such deviations from

established procedure should be

included in the review.

In system audit trails or logs (as

opposed to data audit trails), certain

patterns of activities should be

reviewed. Repeated failed logins,

which may indicate fraudulent

break-in attempts, are a prime

example. Algorithms for detecting

such activities that are built into a

system should be enabled. A review

of the output of such an algorithm

replaces the actual physical review

of the raw audit trail for these

events. Read/write errors to and

from data storage, which could

indicate a breach of data integrity

due to hardware failures, should also

be checked.

Events not included in the list of

critical items that will not improve

patient safety or compliance, or

add value, should be excluded from

any review by default. This action

becomes especially important

for the review of audit trails from

enterprise resource planning (ERP)

software used in the supply chain

Table I: Data integrity challenges in pharmaceutical manufacturing systems.

Review type

System type

Quality control lab

(data acquisition)

Manufacturing

(data acquisition)

Business

(data processing)

Validated state Stable, usually easy to

control and maintain (no

frequent changes)

Stable, usually easy to

control and maintain (for

single-product facilities)

Highly variable, frequent

changes, numerous

interfaces

Audit trails Limited, usually compact

and relatively easy to

analyze

Limited, usually easy to

analyze (operator logs),

critical data in batch

records

Extensive, difficult to

separate by batch/product,

difficult to analyze

Critical a uthorizations

(physical and logical

access)

Diversified, difficult to

manage centrally, frequent

access by diverse people

Limited, easy to manage

(exception: package units,

skids)

Extensive, difficult to

manage and control

To perform meaningful audit trail reviews, it is important to ask what the review aims to accomplish.


ES636545_PTE0715_027.pgs 06.30.2015 01:14 ADV blackyellowcyan


and materials management. When

configured accordingly, these

systems can generate large amounts

of audit-trail data with normal daily

transactions. Business process

steps executed automatically by the

system, such as the promotion of

a document from one status to the

next after an electronic signature

by the user to release a document

for production, can generate many

audit trial entries. In a company

with hundreds of system users, this

activity may result in hundreds of

megabytes of audit trail information

to review. A restrictive filtering

process is needed to eliminate all

non-critical events and focus the

review on the critical entries. On

these types of business systems,

a clear definition of the critical

entries is the only way to perform

a meaningful review in support of

data integrity.

Critical authorizationsAs shown in Table I, data acquisition

systems in manufacturing may

require the lowest amount of

effort to control access security,

because these systems typically

are physically separated from other

systems (non-networked) and, in

many cases, are only accessible

using physical access controls

(badges, keys).

Access to laboratory systems

and processes will be highly varied,

with stand-alone instruments and

linked instrument computers. For

each instrument, the requirements

for data integrity apply, whether the

system complies with 21 CFR Part

11 or the test results are printed

and the electronic information is

discarded. Commonly, access to data

and instruments is based on what

the drug manufacturer considers

to be critical authorizations; these

permissions warrant periodic review.

As with the audit trail events, critical

authorizations must be defined

prior to launching the review cycle

to generate consistent and useful

reviews. Notably, the review of

critical authorizations will not include

analysis for fraudulent access

attempts, but only the status and

history of authorization levels and

issued permissions.

System administrator permissions

for all systems, regardless of the

area in which they are used, should

be reviewed periodically. System

administrations can act outside

enforced business process and

have direct access to database

tables via management tools that

may not include input validation

or other data-integrity protection

safeguards. It is crucial to control

these authorizations to a high degree

to avoid intentional or accidental

data corruption.

Super-user permissions, which

may be needed to change recipes

on process control systems or test

methods on laboratory systems,

also should be considered critical,

because activities of these users

may cause incorrect data further

along the management process.

Authorizations needed to create

records in the system or to initiate

the generation or acquisition of

information need not necessarily be

classed as critical authorizations,

and as such would not be included

in the periodic review (except for

business reasons, such as license

retirement, etc.)

Validated stateA properly validated computer

system or business process will

support the maintenance of data

integrity. It is therefore crucial

that the baseline validation is kept

up-to-date to show that all changes

have been tested in accordance

with assigned risk criteria. Often,

the primary aim of a review of

the validated state of a system

is to show that it still complies

with regulations for computerized

systems, such as 21 CFR Part 11 or

EU GMP Annex 11 (4). For systems

subject to few or even no changes,

there may not be added value

in reviewing this documentation

periodically. Unless there is a

degradation of performance of the

system due to its nature or mode

of action, a review of the validated

state at an appropriate frequency

will confirm the state of control and

compliance required by regulations.

In particular, business systems

such as large-scale ERP or

document management systems are

often subject to frequent changes in

configuration and functionality. For

these types of systems, a periodic

review—including all change

control records, service tickets,

and documentation changes—will

be extensive. Determination of

the cumulative effect of changes

is also difficult and not always

entirely accurate under these

circumstances. It is, therefore,

necessary during collection of

information for the review to only

select changes and modifications

that may have a potential impact

on data integrity for the area

of patient safety and product

quality. For a cGMP determination

of data integrity, human capital

Table II: Suggested review frequencies for software by risk class.

Risk classGood Automated Manufacturing Practices (GAMP 5) Software Category

5 4 3 1

High 3 months 6 months 12 months 24 months

Medium 6 months 12 months 24 months For Cause

Low 24 months 36 months For cause For cause

For all types of reviews and for all types of systems, the actual detection of a data integrity breach should cause process deviations to be raised followed by subsequent corrective and preventive action.




information, or financial data

integrity may not be applicable

and can be excluded from review.

Tickets and change requests in

these areas can be omitted during

such an assessment. It has proven

useful to tag change requests as

GMP-relevant or business-relevant

during an impact assessment by the

quality unit as part of the regular

change control process. Such a

tag will allow easy filtering during

review of the validated state. The

same principle should be applied

to business process deviations or

help-desk tickets.

For all types of reviews and for

all types of systems, the actual

detection of a data integrity breach

should cause process deviations to

be raised followed by subsequent

corrective and preventive

action. This action can include,

if warranted, an increase in the

frequency of the particular review

cycle. Table II offers guidance for

review frequencies, based on the

Good Automated Manufacturing

Practices (GAMP 5) software

categories of a system (5) and

an arbitrary scale of risk (high/

medium/low). The scale should

to be determined according to

the proximity of the system to

the regulated product and by the

potential impact a data integrity

breach would have on patient

safety and product quality.

ConclusionThe number of computerized data

acquisition and processing systems

in the pharmaceutical industry is

growing quickly and with it the

number of records generated that

are inextricably linked with the

regulated products manufactured

by the industry. The situation is

complicated by the integration

of systems, interfaces between

the systems, and conversions,

calculations, and compression

of information that may take

place during transmission. The

knowledge generated from these

data and information is directly

used in the manufacture of drugs.

Data integrity and its practical

maintenance are therefore crucial

to the safety of patients and the

quality of healthcare products. By

using a risk-based approach and the

presented principles, it is possible

to generate meaningful reviews and

proof of data integrity.

References1. Government Printing Office, Code of

Federal Regulations, Title 21, Food and

Drugs (Washington, DC), Part 11, pp.

13465-13466.

2. MHRA, GMP Data Integrity Definitions

and Guidance for Industry, March 2015.

3. ICH, Q9, Quality Risk Management,

step 4 version (2005).

4. EMA, Eudralex Volume 4 Good

Manufacturing Practice, Part 1, Annex

11 Computerised Systems (revision

January 2011), 2011.

5. International Society of

Pharmaceutical Engineering, ISPE

GAMP 5: A Risk-Based Approach

to Compliant GxP Computerized

Systems, 2008. PTE

Continuous monitoring system checklist Yes No

• Will it keep me compliant with all major

regulatory regimes?

• Does the system o�er wireless monitoring?

• Does it automate reporting to save time?

• Is the system quick and easy to install

and validate?

• Is there dedicated support?

• Does the system have a proven track record?

√

√

√√

√

√

www.vaisala.com/cms

Prevent the UnexpectedProtecting Your Critical Assets

24/7 – the Vaisala viewLinc

Monitoring System


API SyntheSIS & MAnufActurIng

Mic

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Despite a few significant investments in continuous

manufacturing facilities by pharmaceutical

companies, including Vertex Pharmaceuticals, Johnson

& Johnson, GlaxoSmithKline, and Novartis (1), the

adoption of flow chemistry for commercial production

of APIs generally remains in the early stages. The US

Food and Drug Administration (FDA) has encouraged

the adoption of continuous manufacturing since 2004,

but specific guidelines are lacking from the agency

and other regulators around the globe. Both former

FDA Commissioner Margaret Hamburg (1) and Center

for Drug Evaluation and Research Director Janet

Woodcock (2) recently have been more vocal about

the issue, particularly in relation to the proposed

21st Century Cures Act. This legislation requires FDA

to support the development and implementation of

continuous manufacturing for drugs and biologicals

as one of several approaches to speeding up drug

development and commercialization (3). In addition

to a lack of comprehensive regulatory guidance,

however, a dearth of industry personnel with expertise

in flow chemistry is a hindrance to rapid adoption of

continuous technologies.

early adopters and fast followers drive change“While the industry as a whole is in the early stages

of adopting flow chemistry for small-molecule API

manufacturing, the early adopters and fast followers

not only recognize that flow chemistry is the future

of manufacturing, but also believe that they can

implement it effectively,” asserts Tim Jamison,

professor of chemistry and incoming department

head at the Massachusetts Institute of Technology

(MIT) and CEO of Snapdragon Chemistry, a new

company dedicated to catalyzing the adoption

of continuous flow synthesis. “Ultimately, when

these companies realize the many benefits of flow

chemistry, including reduced operating costs,

footprint, and capital expenditures combined with

improved process efficiencies, control, and product

quality, investors likely will modify their expectations

and demand this increased value from the industry

as a whole. The rest of the industry will then have to

scramble to catch up, and the early adopters and fast

followers should reap the rewards of their forward-

thinking actions. At that point, the entire industry—

out of necessity to remain competitive—likely would

shift its view on flow technology,” he explains.

Most large pharmaceutical companies, according

to Peter Poechlauer, innovation manager with

Patheon, have at least installed advocate groups

with a mission to showcase successful applications

of flow processes. Dominique Roberge, head of

chemical technologies with Lonza Pharma & Biotech

agrees that flow chemistry has become an accepted

technology for small-molecule manufacturing, largely

for the development of new chemical reactions

that have not been feasible in batch operations, to

reduce the cost of goods, and to decrease capital

expenditures (CAPEX) via process intensification.

“These projects are significantly more focused and

give a better understanding of what is achievable

via flow chemistry. As a result, we have moved past

focusing on feasibility studies only and are now

evaluating projects that are more mature for tech

transfer and scale-up,” he notes.

“The decision to develop a certain step as a

flow process is, however, opportunistic and may

be motivated by the speed provided in early

development, the need for smooth scale-up of

hazardous reactions, and/or the savings in investment

for a new drug whose future is still uncertain,”

Poechlauer observes. In addition, he notes that

these criteria apply to single steps of multi-step

pharmaceutical syntheses, and therefore hybrid

approaches that combine continuous and batch

operations are most common; few companies

have developed end-to-end continuous syntheses

of pharmaceuticals that combine drug-substance

manufacturing and drug-product formulation.

“Continuous flow manufacturing occupies a similar

position to where a technology like spray drying

was 10–15 years ago. It shows great promise but

the ‘mainstream’ commercial viability within the

pharmaceutical industry has yet to mature,” says

Patrick Kaiser, a principal scientist in the process

development business of SAFC. He believes that,

Authorities and early adopters look to speed up the use of continuous API manufacturing.

Lack of Expertise Hinders Adoption of Continuous API Synthesis

cynthia A. challener,

PhD, is a contributing

editor to Pharmaceutical

Technology Europe.

30 Pharmaceutical Technology Europe July 2015 Pharmtech.com


Controlling the Physical

Properties and Performance

of Semi-solid Formulations

through Excipient Selection

Register for free at www.pharmtech.com/pt/physical

EVENT OVERVIEW:

Semi-solid formulations are in a non-equilibrium state composed

of numerous possible microstructures including API polymorphs,

surfactant phases, crystalline lipophiles, polymer networks and lipo-

phile-surfactant gel or liquid crystalline phases. The selection of excip-

ients in topical semisolid formulations can determine the structure of

microscopic phases that form during processing. The infuence of

these phases on the formulation physical properties can be observed

when measuring viscosity and observing microstructure. Exemplary

data will demonstrate how specifc excipients were used to modify

formulation performance, correct formulations that showed aqueous

phase separation or weeping and improve stability.


n Participants will be introduced to some simple case studies

where the choice of excipients and their quantity had a specifc

infuence on semisolid product quality and performance.

n Participants will learn basic methods for observing or

characterizing the infuence of excipients on semisolid behaviors.

n Participants will see how BASF oleochemical-based excipients

and/or polymers have been employed to solve common

formulation problems and to tailor formulations to meet design

criteria.

Who Should Attend:

n Dermatological and Topical Product Development Scientists

n Formulators

n Analytical Chemists who work with topical products

n Pharmaceutical Scientists

n Raw Material QA and QC Specialists

For questions contact Sara Barschdorf at [email protected]

Sponsored by

Presented by

ON-DEMAND WEBCAST Originally aired June 10, 2015

Presenter:

Norman Richardson

Global Development and

Technical Marketing Manager,

Skin Delivery

BASF

Moderator:

Rita Peters

Editorial Director

Pharmaceutical Technology


API Synthesis & Manufacturing

like spray drying, a clear commercial

pathway and, more importantly, a

clear regulatory pathway will drive

more entrants as developers embrace

the technology’s promise. Even so,

Kaiser expects there will be limitations

to its full embrace, because certain

systems lend themselves to be more

relevant to continuous processing,

while others make less sense to

perform via continuous means, and

this dissonance complicates the

pathway forward. “The reality is that

CMOs must embrace such disruptive

technologies moving forward to

ensure long-term competitiveness in

the marketplace,” he concludes.

expanding toolboxA positive indication for the future of

flow chemistry is its increasing use

for different types of reactions and

downstream separation/purification

operations. With respect to chemical

reactions, using flow processes allows

better control of yield and selectivity,

which have a direct influence on

purification and separation steps,

according to Roberge. “The best

approach is to develop new processes

that can and will lead to a significant

improvement in the synthetic

route, but will typically not work

in a traditional batch process,” he

comments. His examples include

various oxidation reactions (with

molecular oxygen or hydrogen

peroxide), azide chemistry, and high-

temperature/pressure reactions

developed via microwave chemistry.

Jamison adds that the use of flow

chemistry for photochemical and

electrochemical reactions is also

exciting, because these reaction

classes are typically difficult to carry

out and control and also challenging

to translate from laboratory scale

to pilot or manufacturing scale, but

afford significant opportunities to

access completely novel chemical

scaffolds and greatly streamline

current synthetic routes. “By using

flow chemistry to gain better control,

predictability, and scalability for

these reaction classes, chemists

can increase their utilization, which

will ultimately result in significant

advances and broader adoption in the

pharma industry,” Jamison states.

Integration of chemical synthesis

reactions in flow with an increasing

diversity of work-up operations in

flow, such as continuous extraction,

membrane processes, and the

crystallization and separation

of solids, is also an important

development, according to

Poechlauer. He further notes that

the application of parallel, analytical

instruments with sufficiently short

response times have been developed,

allowing efficient control of these

processes.

The development of a complete

toolbox of flow reactors that can be

used for all types of reaction rates

and phases (e.g., liquid-liquid, solid-

liquid, etc.) is also necessary for the

broad application of flow chemistry to

be achieved, according to Roberge. To

address some of this need, Lonza has

developed the pulsating coil reactor

for liquid-liquid phase reactions

and an efficient de-plugging system

based on ultrasound technology.

“Ultimately, true innovation in this

field will come from a few key players

in the market who have the variety

of experience and infrastructure to

optimize multiple reaction platforms,”

asserts Roberge.

Shortage of expertiseIn fact, the inadequate supply

of scientific talent and expertise

necessary to implement continuous

flow technology at scale is perhaps

the largest factor hindering more rapid

adoption of flow chemistry for small-

molecule API synthesis, according to

Jamison. “It’s not as simple as asking

current chemists to start working

with continuous flow technology.

That is like asking a saxophonist to

play oboe. While both instruments are

woodwinds, a saxophone uses one

reed, while the oboe uses two. Thus,

saxophonists can certainly become

oboists, but it is not automatic; there

will be a learning curve in most, if not

all cases. Currently, flow chemistry

is generally not in most university

chemistry curricula. Thus, there will

continue to be a lack of expertise

in this area until this situation is

changed,” he explains. “In the long

run, industry demand will accelerate

such changes; as the industry

requires more expertise in this area,

education/training standards will shift

to meet this demand. This shift will

not occur immediately, however, and

there will likely be a short- to mid-

term lack of human resource supply,”

Jamison says.

Rhony Aufdenblatten, manager of

small-molecule business development

with Lonza Pharma & Biotech,

agrees that flow chemistry remains

a specialized technology, because it

requires specific technical know-how

that can only be developed over years

of manufacturing different chemical

products. “The key challenge for any

small-molecule development program

is management of scale-up of the

lab process for industrialization.

Moving this type of scale-up into a

new platform like flow chemistry can

only be handled by the few players

who have experience working with a

variety of chemistries and processes,”

he observes.

Poechlauer is not convinced that

continuous processing is “experts

only” territory any longer, but he also

believes that this perception certainly

affects decisions regarding adoption

of the technology. As a result, he

does believe that CMOs with a proven

track record in continuous processing

may be favored as demand for this

capability increases.

regulatory and infrastructure issuesTwo other factors that are influencing

the rate of adoption of flow chemistry

for API synthesis include a lack of

clear regulatory guidelines and the

existing batch-based manufacturing

infrastructure. Although FDA

representatives recently made

a number of public comments in

support of continuous manufacturing

in the pharmaceutical industry, from a

regulatory standpoint, there remains

a need to develop clear, harmonized

guidelines accepted across the

various regulatory authorities that

will facilitate the development of

continuous manufacturing routes in a

manner that guarantees a consistent

way to monitor/regulate their output,

according to Jamison. In addition,

while there are a growing number

of flow processes being filed with

auditors despite this lack of clarity,

Poechlauer notes that there is little

experience with respect to the

auditing of continuous process steps.

Contin. on page 35

32 Pharmaceutical Technology Europe July 2015 Pharmtech.com


www.cphikorea.comJoin the conversation @cphiww #cphikorea

Are you looking to

grow your business

in a developed

Asian market?

Register

as a visitorusing

media code:

CPKR502

7 - 9 September 2015 • COEX • Seoul

URL: www.cphi.com/korea/visit/register

Organised by

01

02

03

04

South Korea’s generic market is projected to grow on average 5% per year between 2013 – 2018 to a staggering $23.84 Bln.

South Korea closely ranks after China and India as the third “best outsourcing destination” in Asia.¹

Korea Drug Development Fund (KDDF) will promote the development of the Korean biotechnology sector in the Asia Pacific region aiming to produce 10 new treatments by 2019.

Investment in R&D and related facilities is very active and establishment of plants according to the international standardsis increasing.

¹ The changing dynamics of pharma outsourcing in Asia, PwC.


SC

IEP

RO

/ge

tty

ima

ge

s

as newer approaches based on osmotic-controlled

drug delivery.

Prodrugs. The prodrug strategy exploits the

presence of the colonic microflora, which is in the

order of 1011–1012 colony-forming unit (CFU) per

mL in the colon, compared with 103–104 CFU/mL

in the stomach and small intestine (2). To form the

pharmacologically inactive prodrug, the parent drug

is attached to a chemical group, and enzymatic

degradation by the bacteria in the colon then frees the

active drug molecule. Linkages such as azo, amide,

glucuronide, and glycosidic bonds are often used in

prodrug formation for colon-specific drug delivery. Ruiz

et al. reported on the development of a double prodrug

system for colon targeting of benzenesulfonamide

cyclo-oxygenase-2 (COX-2) inhibitors (3). The prodrug

was first activated by azoreductases followed by

cyclization to release the active drug. According to the

researchers, the prodrug demonstrated good stability

in human intestinal extracts and was only activated

under specific conditions of the colon, hence achieving

targeted drug release.

pH- and time-dependent drug-delivery

systems. In this approach, drug release is triggered

by a change in pH as the dosage form passes through

the gut. It is generally accepted that the pH of the

GI tract progressively increases from the stomach

(pH 1–2 in fasted state and pH 4 during digestion)

to the small intestine (pH 6–8). The important

thing is for the formulation to remain intact until

it reaches the colon. Such formulations typically

incorporate polymer coatings that are insoluble in

an acidic environment but become soluble as the pH

increases. Commonly used pH-sensitive polymers

include Eudragit L and S, polyvinyl acetate phthalate,

hydroxyl propyl methyl cellulose phthalate, and

cellulose acetate, to name a few.

Time-dependent systems take a different approach

by delaying drug release after a specific period of

time. Taking into account gastric emptying and

intestinal transit times, swellable systems that

incorporate different combinations of hydrophilic

and hydrophobic polymers as the coating material

are used to adjust the time lag. Recent approaches

often combine both pH- and time-dependent systems

to achieve more targeted drug delivery to the colon.

Ofokansi and Kenechukwu, for example, prepared

ibuprofen tablets using Eudragit EL 100 and chitosan

to form interpolyelectrolyte complexes (4). The

formulation showed pH-dependent swelling

properties and prolonged drug release in vitro (4). The

electrostatic interaction between the carbonyl (-CO-)

group of Eudragit RL 100 and the amino (-NH3+) group

of chitosan was thought to prevent drug release in

the stomach and small intestine, facilitating colon-

targeted drug delivery.

Osmotic-controlled drug delivery. Osmotic

systems are commonly used for controlled-release

purposes but the concept can be applied in colon

drug delivery as well. The system consists of

the drug, an osmotic agent, and a semi-permeable

Oral formulations, which are still the most widely

used dosage forms, can be designed to release

the drug at specific sites of the gastrointestinal (GI)

tract. Today, the colon is becoming a more attractive

target, not only for treating diseases of the colon such

as Crohn’s disease, ulcerative colitis, and colorectal

cancer, but also for GI therapies in general. For

example, colon targeting can be used to systemically

deliver proteins and peptides that are susceptible

to enzymatic degradation in the stomach or small

intestine. This approach has been found to provide

safe and effective therapy with proven bioavailability

enhancement as well as a lower incidence of drug

toxicity and unwanted side effects.

Colon-specific drug delivery exploits the

differences in anatomical and physiological

features of the upper and lower segments of the

gut. Research has shown that the colon is more

responsive to absorption enhancers, protease

inhibitors, and bioadhesive and biodegrable polymers

compared with other regions of the gut (1). The

challenge, however, comes in ensuring that the drugs

are intact when they eventually reach the colon,

which is often a problem with traditional oral dosage

forms. A number of different approaches are being

used to target drug release in the colon. This article

will summarize key trends, including the use of

prodrugs, pH- and time-dependent systems, as well

Adeline Siew, PhD

Mission Possible:Targeting Drugsto the ColonProdrugs and drug-delivery systems controlled by time, pH,

and osmosis, are being used to prevent drug degradation in the

stomach and small intestine and ensure drug release in the colon.

34 Pharmaceutical Technology Europe JuLy 2015 PharmTech.com


Drug Delivery

membrane with an orifice for drug

release. An additional enteric coating

is applied on top of the membrane

to prevent drug release in the

stomach and upper GI tract. As

the dosage form enters the small

intestine, the increase in pH causes

the enteric coating to dissolve,

exposing the semi-permeable

membrane. Water enters the drug

core and the expanding volume

forces the drug out the osmotic

system through the orifice.

A number of research groups

are working on the development

of innovative osmotic tablets for

the treatment of inflammatory

bowel disease. Chaudhary et al., for

example, developed microporous

bilayer osmotic tablets of dicyclomine

hydrochloride and diclofenac

potassium for colon targeting (5).

The bilayer coating consisted of

a microporous semipermeable

membrane and an enteric polymer.

The tablets showed acid resistance

and time release in in-vitro dissolution

studies, demonstrating the potential

for colon-specific drug delivery to

treat irritable bowel syndrome.

Nath et al. incorporated Sterculia

gum, which is a polysaccharide, into

osmotic tablets for colon-specific

drug delivery of azathioprine (6).

Sterculia gum is digested by the

colonic enterobacteria and swelling

of the polysaccharide forces the

drug out of the tablet core. To ensure

that drug release does not occur in

the upper GI regions, a double-layer

coating of chitosan/Eudragit RLPO

(ammonio-methacrylate copolymer)

and enteric polymers is used to

impart acid- and intestinal-resistant

properties to the tablet.

In short, the colon offers an

alternative drug-delivery approach

for acid-labile drugs such as proteins

and peptides, drugs that degrade

in the stomach and small intestine

or undergo extensive first pass

metabolism, as well as for topical

treatment of inflammatory diseases

of the colon. While progress is being

made in achieving more specific

targeting of drugs to the colon, the

complexity of these drug delivery

systems will require validated

dissolution methods and establishing

in-vitro/in-vivo correlation.

References1. V. Sinha et al., Crit Rev Ther Drug

Carrier Syst. 24 (1) 63–92 (2007).

2. V.R. Sinha and R. Kumria, Pharm Res.

18 (5) 557–564 (2001).

3. J.F. Ruiz et al., Bioorg Med Chem Lett.

21 (22) 6636–6640 (2011).

4. K.C. Ofokansi and F.C. Kenechukwu,

ISRN Pharm. online, DOI:

10.1155/2013/838403, 6 Aug. 2013.

5. A. Chaudhary et al., Eur J Pharm

Biopharm. 78 (1) 134–140 (2011).

6. Nath et al., PDA J Pharm Sci Technol.

67 (2) 172–184 (2013). PTE

API Synthesis & Manufacturing — contin. from page 32

The International Conference

on Harmonization (ICH) may be

an effective body for achieving

international guidelines. The

organization may in fact be making

continuous flow manufacturing a focus

issue over the next year to 18 months.

The impact of existing batch plants

is less straightforward. For companies

with unused batch capacity,

Aufdenblatten notes that additional

motivation for further investment into

large-scale flow chemistry will be

needed to overcome the additional

CAPEX for flow infrastructure.

“Typically, a gain in yield of 2–3%

will not be sufficient; reduced

cost of goods, safer processes,

and breakthroughs in process

platforms must also be considered,”

he explains. Jamison points out,

though, that existing infrastructure

is in various stages of maturity, and

new capacity (whether batch or

continuous) could be established

naturally, with continuous plants

being built in place of new batch

plants, as appropriate. “In addition,”

he says, “continuous manufacturing

plants could have a 10- to 100-fold

smaller footprint than a batch plant

of comparable output. Therefore,

the CAPEX investment is smaller,

which might sway the economic

analysis to favour the business case

of mothballing a significant number of

existing batch-mode plants.”

The mentality of the process

development function must also

be considered, according to Kaiser.

The use of flow chemistry earlier

in development requires both the

innovator and CMO to be open to

using continuous systems as an

option in their process development

efforts. Doing so potentially requires

developing an initial batch process

backed up by a second-generation

flow process, perhaps simultaneously

if the drug is on an accelerated

approval pathway, which is not a

small shift in today’s “fast-fail” drug

development business. “Development

companies are generally averse

to investing too much in the

manufacturing process until there

is good clinical data to show

manufacturing on a larger scale is

necessary. Unfortunately, waiting too

long to develop a continuous process

also complicates a company’s

regulatory strategy and potentially

a challenge with different impurity

profiles from different manufacturing

processes,” he comments. The best

strategy to combat this challenge,

according to Kaiser, is to have

experienced flow chemistry experts

recognize where continuous systems

provide the greatest opportunity

for results early on in the process

development effort.

References1. J.D. Rockoff, “Drug Making Breaks

Away From Its Old Ways,” The Wall

Street Journal, www.wsj.com/articles/

drug-making-breaks-away-from-its-

old-ways-1423444049, accessed

2 June 2015.

2. J. Wechsler, “Congress Encourages

Modern Drug Manufacturing,” www.

pharmtech.com/congress-encourages-

modern-drug-manufacturing, accessed

2 June 2015.

3. Energy & Commerce Committee,

United States House of

Representatives, “Full Committee Vote

on the 21st Century Cures Act,”

19 May 2015, http://energycommerce.

house.gov/markup/full-committee-

vote-21st-century-cures-act, accessed

2 June 2015. PTE

Pharmaceutical Technology Europe JuLy 2015 35



PEER-REVIEWED

Jigar N. Shah, PhD,* is assistant professor at Nirma University’s Institute of

Pharmacy’s Department of Pharmaceutics in Ahmedabad, Gujarat, India. He can be

reached at [email protected] or [email protected].

Rakesh Patel, PhD, is professor at S.K. Patel College of Pharmaceutical Education &

Research, Ganpat University, Kherva, Gujarat, India.

Hiral J. Shah, PhD, professor, J. Arihant School of Pharmacy & Bioresearch Institute,

Adalaj, Gandhinagar, Gujarat, India.

Tejal A. Mehta, PhD, is professor, Institute of Pharmacy, Nirma University,

Ahmedabad, Gujarat, India.

*To whom all correspondence should be addressed.

Submitted: October 8, 2014. Accepted: November 17, 2014.

Beyond the Blink: Using In-Situ Gelling to Optimize Opthalmic Drug DeliveryDelivery systems that allow drugs to be administered as liquids, but form gel within the eye, promise to improve efficacy and patient compliance. Jigar N. Shah, Rakesh K. Patel, Hiral J. Shah, and Tehal A. Mehta

Conventional ophthalmic solutions frequently show poor

bioavailability and a weak therapeutic response because

they are often eliminated before they can reach the cornea,

when patients blink or their eyes tear. Use of in-situ gel

forming solutions may help improve performance and patient

compliance. These solutions are delivered as eye drops, but

undergo a sol-gel transition in the conjunctival sac (cul de

sac). This article describes how an ion-activated in-situ gelling

system was designed to deliver an ophthalmic formulation of

the antibacterial agent, Levofloxacin.

The delivery system uses gellan gum, a novel ophthalmic

vehicle that gels in the presence of mono or divalent cations

in the lacrimal fluid. This gum was used alone and combined

with sodium alginate as a gelling agent and hydroxypropyl

methylcellulose (HPMC) Methocel F4M as a viscosity enhancer.

A 32 full factorial design approach was used, with two polymers:

Gelrite and HPMC, as independent variables. Gelling strength,

bioadhesion force, rheological behaviour, and in-vitro drug

release after 10 h were selected as dependent variables. Both

in-vitro release studies and rheological profile studies indicated

that the combined Gelrite–HPMC solution retained the drug

better than the gellan gum alone or a combination of gellan gum–

alginate–HPMC. The developed formulations were therapeutically

efficacious and provide sustained release of the drug over a 12-h

period in vitro. These results demonstrate that the Gelrite–HPMC

Methocel F4M mixture can be used as an in-situ gelling vehicle to

enhance ophthalmic bioavailability and patient compliance.

Opthalmic drug delivery systems, such as eye

drops, ointments, and soft gel capsules, are

typically used to treat diseases of the eye.

However, the eye’s protective mechanisms often

reduce their therapeutic effect. When a drug

solution is dropped into the eye, there is typi-

cally a 10-fold reduction in the drug concentra-

tion within 4–20 min, due to the effective tear

drainage and blinking action (1). The cornea’s

limited permeability contributes to the low

absorption of ocular drugs. Due to tear drainage,

most of the administered dose passes via the

nasolacrimal duct into the gastrointestinal tract,

leading to side effects (2). Rapid elimination of

both the solutions and the suspended solid

administered often results in blurred vision, poor

patient acceptance, and short duration of the

therapeutic effect, making more frequent dosing

necessary (3). New preparations have been

developed to prolong the contact time on the

ocular surface and slow down drug elimination

(4, 5). Ocular inserts (5) and collagen shields (6)

can also be used, but they pose challenges.

These delivery challenges can be overcome

by using in-situ gel-forming ophthalmic drug

delivery systems prepared from polymers that

exhibit reversible phase transitions (sol–gel–sol)

and pseudoplastic behaviour. Such formulations

minimize interference with blinking (7).

Changes to the gel phase (8) can increase

pre-corneal residence time and enhance ocular

bioavailability. Three types of systems have

been used: pH-triggered systems including

cellulose acetate hydrogen phthalate latex (9, 10)

and carbopol (11–15); temperature-dependent

systems including pluronics (7, 16–20), tetronics

(21, 22), and polymethacrylates (23); and ion-

activated systems including Gelrite (24–26),

gellan (27–28), and sodium alginate (29).

The authors used an ion-activated in-situ

gelling system to deliver Levofloxacin, a fourth-

CITATION: When referring to this article, please cite it as J. Shah et al., “Beyond the

Blink: Using In-Situ Gelling to Optimize Opthalmic Drug Delivery,” Pharmaceutical

Technology 39 (7) 2015.



Optimizing Opthalmic Formulation

generation fluoroquinolone anti-infective agent, which can

be used to treat conditions including acute and subacute

conjunctivitis, bacterial keratitis, and keratoconjunctivitis.

The goal was to demonstrate prolonged action and show

antibacterial activity against gram-positive and gram-

negative bacteria directly at the site of infection without

loss of dosage. The combination of Gelrite (gellan gum)

and hydroxypropyl methylcellulose (HPMC) (Methocel F4M)

was used to prepare the gelling system, which was used

with and without sodium alginate to prepare Levofloxacin

eye drops (0.5% w/v). These drops would undergo gelation

when instilled into the cul-de-sac of the eye, and provide

controlled release of the drug in treatment of ocular

infections.

Materials and methods.

Materials. Levof loxacin was obtained from Zydus

Healthcare, Gelrite from CP Kelco, and HPMC (Methocel

F4M) was provided by Colorcon Asia Pvt. Ltd. All other rea-

gents, chemicals, and solvents were of analytical grade.

Methods. Method of preparation. Gelrite-based in-situ

gelling systems were prepared by dissolving gellan, alone

and combined with sodium alginate and/or HPMC in hot

phosphate buffer (pH 7.4, 70˚C), by continuous stirring at

40-45 ˚C for 24 h, as shown in Table 1. Then the weighed

quantities of levofloxacin (0.5% w/v), mannitol, and

preservatives, such as methyl paraben and propyl paraben,

were added to the solution and stirred until dissolved. The

solutions were then transferred into previously sterilized

amber-colored glass vials, capped, and sealed with aluminum

caps. The formulations were sterilized by terminal autoclaving

at 121 ˚C, 15 PSI for 20 min. The sterilized formulations were

stored in a refrigerator at 4–8 ˚C until use.

Experimental design

A 32 full factorial approach was taken to design the gel-

ling system. Two factors were selected, and a total of nine

experimental trials were performed using all possible com-

binations. The concentrations of Gelrite (cation-sensitive

in-situ gelling polymer) as X1 (0.3, 0.4, and 0.5%, m/V) and

HPMC (viscosity imparting agent) as X2 (0.3, 0.5, and 0.7%,

m/V) were selected as independent variables.

Gel strength (GS in s), bioadhesion force (BF in N), viscosity

(VI) in Pa.s, and cumulative percent drug release after

10 h (CR10) were selected as dependent variables. The

design is shown in Table II. Equation 1 summarizes the

experimental design, using two independent variables and

three levels (low, medium, and high) of each variable:

Y = b0 + b

1X

1 + b

2X

2 + b

11X

11 + b

22X

22 + b

12X

1X

2 (Eq 1)

where Y is the dependent variable, b0 is the mean

response of the nine runs, and bi is the estimated coefficient

for factor Xi.

The main effects (X1 and X

2) represent the average result

of changing a factor at a time. The interaction term (X12

)

shows how the response changes when the factors are

simultaneously changed. Polynomial terms (X11

and X22

) are

included to investigate nonlinearity.

Statistical analysis and two-way analysis of variance

(ANOVA) were used to evaluate the significance of each

factor to the response at different levels. Three-dimensional

response surface plots and two-dimensional contour plots

of the data were generated using Design Expert software

(Version 8).

Evaluation of formulation

The following were used to evaluate the formulation.

Gelation studies were carried out in a vial containing

the gelation solution and simulated tear fluid (STF) solution,

composed of 0.670 g of sodium chloride, 0.200 g of sodium

bicarbonate, 0.008 g of calcium chloride dehydrate, and

purified water, quantum satis to 100 g.

The preparation was carefully taken into the vial using a

micropipette, and 2 mL of gelation solution (STF) was added

slowly. Gelation was assessed by visual examination (26).

Rheological studies. Viscosities of sample solutions were

measured in a Brookfield synchrolectric viscometer (LVDVI

Table I: Composition of prepared in-situ gelling systems.

Batch Gellan (%w/v) SA (%w/v)* HPMC (%w/v) Gelling capacity Drug content (%)

LV 0.2 - - + 97.23±1.27

LV1 0.3 - - ++ 98.35±1.09

LV2 0.3 0.27 - +++ 99.38±0.94

LV3 0.3 0.29 0.5 +++ 98.17±1.12

LV4 0.3 - 0.5 +++ 99.47±0.89

LV5 0.4 - - +++ 99.25±0.79

LV6 0.4 0.27 - +++ 99.52±0.95

LV7 0.4 0.29 0.5 +++ 98.93±0.67

LV8 0.4 - 0.5 +++ 99.42±1.13

+ gels slowly and dissolves; ++ gelation immediate and remains for a few hours; +++ gelation immediate and remains for an extended period.*Amount of Sodium alginate was adjusted (equivalent to 0.25% w/v)




prime) at different angular velocities at a temperature of

37±1˚C. The angular velocity was increased from 0.5 to 100

rpm with 6 s between two speeds. The sequence of the

angular velocity was reversed. The average of two readings

was used to calculate viscosity. Evaluations were conducted

in triplicate (26).

Drug content uniformity. Vials containing the

formulation were shaken for 2–3 min, and the preparation

was transferred aseptically to sterile volumetric flasks. The

final volume was made up with phosphate buffer pH 7.4. The

concentration of Levofloxacin present was determined at

287 nm using UV spectrophotometry (26).

In-vitro drug release studies. The studies were carried

out using a Franz diffusion cell, with STF (pH 7.4) as

dissolution medium. The cell consists of glass donor and

receptor compartments, separated by a dialysis membrane.

The optimized formulation was placed in the donor

compartment, and freshly prepared STF was placed in the

receptor compartment. The whole assembly was placed in a

temperature-controlled shaker water bath maintained at 37

˚C ± 0.5 ˚C. A sample (1 mL) was withdrawn at predetermined

time intervals up to 24 h and the same volume of fresh

medium was replaced. The withdrawn samples were

analyzed by UV spectrophotometer at 287 nm.

Bioadhesive strength measurement. Freshly excised

goat conjuct ival membrane was used to measure

bioadhesive strength. The membrane was placed in an

aerated saline solution at 4 ˚C until used. It was tied to the

lower side of the hanging polytetrafluoroethylene (PTFE)

cylinder using thread, and the cylinder was fixed beneath of

left pan of a pan balance. The formulation was placed into a

sterile petri plate that was kept on the platform beneath the

left pan. The two sides of the pan balance were balanced by

keeping a 2-g weight on the right pan.

The 2-g weight was then removed, lowering the left

pan and allowing the membrane to come in contact with

the formulation. The membrane was kept in contact

with the formulation for 5 min. Weight was slowly added

to the right pan slowly, in increments of 0.5 g, until the

formulation detached from the membrane surface. The

excess weight on the right pan was taken as the measure

of the bioadhesive strength. The force of adhesion was then

calculated using the following formula (13).

Force of adhesion = Bioadhesive strength x 9.81 / 1000.

Infrared spectroscopy and DSC studies. Infrared (IR)

spectroscopy and differential scanning calorimetry (DSC)

were then used to analyze the pure drug, gellan, HPMC,

physical mixture of drug-gellan-HPMC, and optimized

formulation. Resulting spectra were then compared with

reference spectra.

Antimicrobial ef f icacy studies. The solut ion’s

antimicrobial efficacy was determined using agar diffusion

and commercial Levofloxacin eyedrops as a control. The

sterilized solutions were poured into cups bored into sterile

agar nutrient seeded with test organisms (Pseudomonas

aeruginosa and Staphylococcus aureus). After allowing

diffusion of the solutions for two hours, the plates were

incubated at 37 ˚C for 24 h, and the zone of inhibition

(ZOI) was measured around each cup and compared with

control’s ZOI. The entire process, except for the incubation,

was carried out under laminar flow units in an aseptic area

(Class 10,000). Each solution was tested three times. Both

positive and negative controls were maintained throughout

the study (26).

In-vivo ocular irritation and stability studies. In-vivo

ocular irritation studies were performed using the Draize

Table II: Composition and results of 32 full factorial design batches.

Batch

Code

Variable levels Actual Units

GS (s) BF x 105(N)VI x 10

(Pa.s)CP10 (%)

Gelrite X1

HPMC F4M

X2

X1 (% m/V) X

2 (% m/V)

LF1 -1 -1 0.3 0.3 105 ±1.12 1955±26.09 1200 99.56

LF2 -1 0 0.3 0.5 108±2.02 1922±78.01 1556 96.45

LF3 -1 +1 0.3 0.7 117±2.68 2020±78.01 1867 90.15

LF4 0 -1 0.4 0.3 111±0.68 2740±78.01 1339 94.86

LF5 0 0 0.4 0.5 116±1.13 2969±26.09 1794 90.59

LF6 0 +1 0.4 0.7 125±2.02 3132±128.1 2121 87.66

LF7 +1 -1 0.5 0.3 118±2.68 4603±128.1 1534 88.43

LF8 +1 0 0.5 0.5 122±3.04 4701±26.09 1984 75.15

LF9 +1 +1 0.5 0.7 134±0.97 4832±26.09 2429 68.39

LF10* -0.5 0.5 0.35 0.6 112±1.53 2800±78.01 1850 92.62

LF11* 0.5 -0.5 0.45 0.4 113±1.02 3400±128.1 1550 87.60

GS is gel strength; BF is bioadhesion force; VI is viscosity; CP10 is cumulative percentage drug release after 10 h. * indicates check point batch


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technique (30) and guidelines set by the Organization for

Economic Cooperation and Development (OECD) (31). Six

albino rabbits, each weighing 2–3 kg, were used for this

study. The sterile formulation was administered to the

test rabbits twice a day for 21 days and the rabbits were

observed periodically.

International Council for Harmonization (ICH) guidelines

were used to determine the optimized formulation’s stability.

The gel was stored in a stability chamber at ambient

humidity between 2 ˚C to 8 ˚C, ambient temperature at

40 ˚C ±0.5 ˚C for six months. The samples were withdrawn

at regular intervals and analyzed. The logarithms of percent

drug remaining were calculated and plotted against time in

days. The degradation rate constant was calculated using

the equation: slope = k/2.303, where k is a degradation rate

constant. The shelf life of the developed formulation was

calculated using the Arrhenius plot.

Results and discussion

Composition of various batches of the prepared in-situ gel-

ling formulations are shown in Table 1. In the batch con-

taining gellan alone, the concentration of gellan was kept at

a maximum of 0.4% (w/v). Higher concentration beyond 0.4%

caused gelation upon cooling to 40 ˚C.

In the combination batches, the concentration of gellan

was varied and the concentration of sodium alginate

was kept at approximately 0.25% (by compensating the

concentration difference due to reduction in viscosity after

autoclaving for sodium alginate) to give a maximum of 0.65%

polymer concentration, because an increase beyond this

concentration resulted in gelation during formulation.

To maintain the proper pseudoplastic behaviour of

formulation, HPMC was used with gellan alone and with

combination of gellan and sodium alginate. The drug

content and gelling capacity of the formulations were

found to be satisfactory as mentioned in Table I, and the

formulations were liquid at both room temperature and

when refrigerated. Viscosity and gelling capacity (speed

and extent of gelation) are

the most important criteria

for any in-situ gelling system.

A l l b a t c h e s ex h ib i t e d

pseudoplast ic behav iour,

as showed in Figure 1. All

batches showed low viscosity

at high shear rate and high

viscosity at low shear rate.

Autoclave process had not

af fected the v iscosit y of

the formulations, except for

those containing sodium

alg inate where v iscosit y

was reduced around 8–15%.

Therefore, the concentration

o f sod ium a lg inate was

adjusted to compensate (25).

All measurements were taken three times and showed good

reproducibility.

Figure 2 shows the cumulat ive percentage of

Levofloxacin released versus time profiles for batches

LV1 to LV8. These results suggested that Levofloxacin

was sustainably released from formulation LV8, when

the content of gellan gum was 0.4% and 0.5% of HPMC

Methocel F4M (Table I). A similar release pattern is reported

for pilocarpine (32) from alginate systems, wherein an

inverse relationship between drug release and polymer

concentration was observed.

Experimental design

Based on studies of response variables, the polynomial rela-

tionships are expressed in Equations 2 to 5.

GS (gel strength) = 115.33 + 7.33*X1 + 7X2 (Eq. 2)

BF (bioadhesion force) = 3069.44 + 989.83*X1 +

314.33*X2 + 116*X1^2 (Eq. 3)

VI (viscosity) = 1771.11 + 220.66*X1 +

390.66*X2 + 57 X1*X2 (Eq. 4)

CR10 (cumulative

percentage drug

release after 10 hs) = 90.51 – 9.03*X1 – 6.1*X2 (Eq. 5)

All the polynomial equations were found to be statistically

significant (P < 0.05) and in good agreement with results.

From Equation 2, it can be concluded that both gellan gum

and HPMC significantly affect the gelling strength (25, 13).

Formulation batches LF1 and LF2 showed poor gelation

strength, which might be due to the minimum amount of

gellan and/or HPMC.

The results are shown in Table II. The studies showed

that, in the presence of HPMC, as the amount of gellan

increased, gel strength increased as well; this effect must

be due to the additional effect of concentration of polymer.

Figure 3(a) shows the response surface plot illustrating

the effect of gellan gum and HPMC on the gelling strength.

1800

1600

1400

1200

1000

800

600

400

200

0

0 10 20 30 40 50 60 70 80 90 100

LV1

LV2

LV3

LV4

LV5

LV6

LV7

LV8Vis

cosi

ty (

cp)

Shear rate (rpm)

Rheological profles of batches LV1 to LV8

Figure 1: Rheological profiles of the formulations LV1-LV8.

Al

l f

igu

re

s A

re

co

ur

te

sy

of

th

e A

ut

ho

rs

.




Studies confirmed that both

polymers significantly affect

the gelling strength.

F r o m E q u a t i o n 3 , i t

c a n b e c o n c l u d e d t h a t

b o t h p o l y m e r s h a v e a

p r e d o m i n a n t e f f e c t o n

b i o a d h e s i ve f o rc e . T h e

f o r m u l a t i o n c o n t a i n e d

ge l l an g um, w h ich i s a

mucoadhesive agent. Studies

show that polymers with

charge can serve as good

mucoadhesive agents. I t

has also been reported that

po l yan ion po l y mers a re

more effective bioadhesives

than polycations or nonionic

p o l y mer s (3 3 , 3 4) . T h i s

po lymer adheres to the

mucin of the eye, which

leads to prolonged retention of the formulation inside an

eye (13). Figure 3(b) depicts the response surface plot,

showing the influence of both polymers on bioadhesion

force. The studies confirmed that, as the concentration

of gellan gum or HPMC is increased, bioadhesion also

increases.

Equation 4 shows that HPMC has a predominant effect

on viscosity compared to gellan gum. Normally, water-

soluble polymers such as HPMC produce two effects:

• Lowering surface tension and improving mixing with the

precorneal tear film

• Increasing viscosity and prolonging contact time, thereby

resisting drainage of drug from eye (13).

Gellan gum can significantly increase viscosity of the

formulation upon exposure to lachrymal fluid. So, by

optimizing the concentration of HPMC viscosity-enhancing

agent, one can decrease the amount of gellan gum in the

preparation to improve patient compliance. Figure 3(c)

shows the response-surface plot of effect of gellan gum

and HPMC on viscosity. From Equation 5, gellan gum and

HPMC are inversely related to the amount of drug released.

The results of in-vitro release studies show that the

formulations retain drug for the duration of the study

(12 h). The movement of the eyelid and eyeball provide

shearing action for faster dissolution of gels in the cul-

de-sac. Figure 3(d) depicts the response-surface plot,

showing the influence of both polymers on drug release

after 10 h respectively. Checkpoint batches LF10 and LF11

were prepared (Table II) to validate the evolved model.

The actual values of GS, BF, VI, and CR10 of batches LF10

and LF11 are given in Table III. Checkpoint batches were

found in good agreement with the actual values. Results of

ANOVA are shown in Table IV.

Release of an optimized batch fitted to a Higuchian matrix

equation showed a high R-squared value (0.99), least SSR

value, and F value {21} as compared to other batches. Thus,

it can be concluded that release of drug was based on a

Higuchian-matrix, diffusion-controlled mechanism.

Bioadhesive strength and thermogram results

The bioadhesive strength measurement of designed

batches is shown in Table II . Dif ferential scanning

calorimetry (DSC) thermograms showed characteristic

peaks of Levofloxacin at 230.50˚C and 111.55˚C, gellan gum

at 266.11˚C, and HPMC at 288.55˚C and 79.79 ˚C (Figure 4).

The peak of Levofloxacin was found to be reduced in

intensity in physical mixture of drug, gelling agent, and

polymer (Figure 4e) and could not be seen in optimized

formulations of DSC thermogram (Figure 4c), indicating the

entrapment of drug in the in-situ matrix gel system of gellan

gum and HPMC.

The optimized formulation (LF5) showed antimicrobial

activity when tested microbiologically by the cup-plate

technique. Clear ZOIs were obtained in the case of the

optimized formulation and marketed eye drops.

The diameters of the ZOIs produced by the optimized

formulation against both test organisms were either on par

or higher than those produced by marketed eye drops as

shown in Table V. The antimicrobial effect of levofloxacin

gel formulation is probably due to its rapid initial release

into the viscous solution and followed by formation of a

drug reservoir that attributed to the slow and prolonged

diffusion from the polymeric solution due to its higher

viscosity (26).

Ocular i r r i tat ion studies (35) indicated that the

formulation is well tolerated by rabbit eyes (36). No ocular

damage or abnormal clinical signs were observed (37).

The optimized formulation of Levofloxacin was kept for

stability studies at refrigeration temperature (4 ˚C), ambient

temperature (25 ˚C), and elevated temperature (40 ˚C) for a

100

90

80

70

60

50

40

30

20

10

0

LV1

LV2

LV3

LV4

LV5

LV6

LV7

LV8

0 2 4 6 8 10 12

CPR

(%

)

Time (Hrs)

In vitro release profles of LV1 - LV8

Figure 2: In-vitro release profile of prepared gelling systems of Levofloxacin LV1 – LV8.




Table V: Antimicrobial efficacy of optimized formulation.

Concentration

(μg/ml)

Zone of Inhibition (cm) (% effciency)

STD LF5

S. aureus

1 1.4 1.5 (107)

10 2.0 2.4 (120)

100 3.2 3.9 (121.88)

P. aeruginosa

1 1.4 1.6 (114.3)

10 2.2 2.5 (113.63)

100 3.8 4.4 (115.8)

STD = standard (commercial eye drops of levofoxacin);

LF5 = optimized formulation from design shown in Table II.

Values in parenthesis indicate the percent effciency;

percent effciency was calculated by (ZOI of test/ZOI of

standard) x 100.

period of six months. Samples were withdrawn at regular

time intervals and were evaluated for appearance, gelation

studies, drug content, and in-vitro drug release.

Stability studies

The formulation was found to be sterile at the end of six months.

The drug degraded to a negligible extent and the degradation

rate constant for optimized formulation was very low (1.12 x

10-4). Because the overall degradation is <5%, a tentative shelf

life of two years may be estimated the formulation (13).

Table III: Comparison of the actual value with predicted

values of checkpoint batches.

Actual values

Batch

codeGS (s) BFx105 N

VI x 10

(Pa.s)CP10 (%)

LF10 112 2800 1850 92.62

LF11 113 3400 1550 87.60

Predicted values

LF10 115.66 2874.9 1815 91.67

LF11 116 3235.04 1645 88.74

GS is gel strength; BF is bioadhesion force; VI is viscosity;

CP10 is cumulative percentage drug release after 10 h.

Table IV: Analysis of variance for dependent variables of

the 32 full factorial design.

Source F-value R2 P

Gel strength (GS) 287.4 0.998 0.00032

Bioadhesion Force (BF) 1301.908 0.999 0.000033

Viscosity (VI) 559.04 0.999 0.00012

CP10 (%) 17.65 0.970 0.0196

F is Fischer’s ratio, p is signifcance level, CP10 is cumula-

tive percentage drug release after 10h.

(d)

3D surface plot of drug release in 10hr

105

100

95

85

75

65

90

80

70

0.5Conc of HPMC

Conc

of G

elrite

0.50.0

0.0

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-0.5

-1.01.0

-1.0

Rel in

10h

r

3D Surface response for gelation

140

135

125

115

105

100

0.5

Conc of HPMC

Conc of G

elrit

e

0.5

0.0

0.0

-0.5

-0.5

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(a)

1.0

-1.0

Gela

tio

n

130

120

110

3D surface plot of bioadhesive force

5000

4000

3000

2000

4500

3500

2500

1500

0.5

Conc of HPMC

Conc of G

elrit

e

0.5

0.0

0.0

-0.5

-0.5

-1.0

(b)

1.0

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ad

hesi

ve

3D surface plot of viscosity

2600

2400

2200

2000

1800

1600

1400

1200

1000

0.5

Conc of HPMC

Conc of G

elrit

e

0.5

0.0

0.0

-0.5

-0.5

-1.0

(c)

1.0

-1.0

Vis

cosi

ty

Figure 3. Response surface plot for effects of the

amount of Gelrite and HPMC Methocel F4M on (a) gel

strength; (b) bioadhesive force; (c) viscosity; (d)

cumulative percentage drug release after 10 h.




Conclusion

An ion-activated in-situ gel formulation of Levofloxacin was

successfully formulated using gellan gum in combination

with HPMC. The formulation underwent gelation in the

conjunctival sac (cul-de-sac), allowing for sustained drug

release over a 12-h period without any adverse effect to the

ocular tissues.

Stability data confirmed that the formulation is stable

for a six-month period in given storage conditions. This

new formulation can enhance bioavailability through its

sustained drug release, higher viscosity, longer pre-corneal

residence time, and better miscibility with the lacrimal fluid.

These benefits promise to improve patient acceptance and

compliance.

References

1. D.M. Maurice, “Kinetics of topically applied ophthalmic drugs,” in

Ophthalmic Drug Delivery Biopharmaceutical, Technological and Clinical

Aspects, M.F. Saettone, M. Bucci, and P. Speiser, Eds. (Fidia Research

Series, Padova: Liviana Press, Springer, New York, 1987), pp. 19-26.

2. D.L. Middleton, S.S. Leung, and J.R. Robinson, “Ocular bioadhesive

delivery systems,” in Bioadhesive Drug Delivery Systems, V. Lenaerts,

and R. Gurny, Eds. (Boca Raton, FL: CRC Press, 1st ed., 1990), pp. 179-

202.

3. O. Olejnik, “Conventional systems in ophthalmic drug delivery systems,”

in Ophthalmic Drug Delivery Systems, A.K. Mitra, Ed. (Marcel Dekker,

New York, 1993), pp. 179-193.

4. C.L. Boularis, et al., Prog. Retin. Eye Res. 17 (1), 33-58 (1998).

5. S. Ding, Pharm. Sci. Technol. Today 8 (1), 328-335 (1998).

6. J.M. Hill et al, “Controlled collagen shields for ocular delivery,” in

Ophthalmic Drug Delivery Systems, A.K. Mitra, Ed. (Marcel Dekker, New

York 1993), pp. 261–275.

7. A.H. El-Kamel, Int. J. Pharm. 241 (1) 47-55 (2002).

8. O. Sechoy, et al., Int. J. Pharm. 207 (1-2) 109-116 (2000).

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10. R. Gurny, T. Boye, and H. Ibrahim, J. Contr. Rel. (2), 353-361 (1985).

11. B. Srividya, et al, J. Contr. Rel. 73 (2-3), 205–211 (2001).

12. D. Aggarwal and I.P. Kaur, Int. J. Pharm. 290 (1-2) 155-159 (2005).

13. Y. Sultana et al., Pharm. Dev. Technol. 11 (3) 313-319 (2006).

14. C. Wu et al., Yakugaku Zasshi 127 (1) 183-191 (2007).

15. H.R. Lin and K.C. Sung, J. Contr. Rel. 69 (3) 379-388 (2000).

16. S.C. Miller and M.D. Donovan, Int. J. Pharm. (12), 147-152 (1982).

17. S.D. Desai and J. Blanchard, J. Pharm. Sci. 87 (2) 226-230 (1998).

18. K.Y. Cho et al., Int. J. Pharm., 260 (1), 83-91 (2003).

19. M.K. Yoo et al., Drug Dev. Ind. Pharm. 31 (4-5) 455-463 (2005).

20. H. Qi et al., Int. J. Pharm. 337 (1-2) 178-187 (2007).

21. M. Vadnere et al., Int. J. Pharm. 22 (2-3) 207-218 (1984).

22. C.W. Spancake et al, Int. J. Pharm. 75 (2-3) 231-239 (1989).

23. G.H. Hsiue et al., Biomaterials 24 (13), 2423-2430 (2003).

24. A. Rozier et al., Int. J. Pharm. 57 (2), 163-168 (1989).

25. J. Balasubramaniam et al, Acta Pharm. 53 (4) 251-261 (2003).

26. Balasubramaniam and J.K. Pandit, Drug Deliv. 10 (3) 185-191 (2003).

27. Y.D. Sanzgiri et al., J. Contr. Rel. 26 (3) 195-201 (1993).

28. J.N. Shah et al, PharmaInfo.net, 5 (6) 2007 www.pharmainfo.net/

reviews/gellan-gum-and-its-applications-%E2%80%93-review, 12 Sep.

2010.

29. Z. Liu et al., Int. J. Pharm. 315 (1-2) 12-17 (2006).

30. J.H. Draize et al, J. Pharmacol. Exp. Ther. 82 (3) 377–390 (1944).

31. OECD Publication Office (Paris, Oct. 2012) Guidelines for testing the

chemicals, Section 4, Test No. 405: Acute eye irritation/corrosion.

32. S. Cohen et al., J. Control. Rel. 44 (2-3) 201–208 (1997).

33. K. Park and J.R. Robinson, Int. J. Pharm. 19 (2) 107–127 (1984).

34. S. Wee and W.R. Gombotz, Adv. Drug Deliv. Rev. 31(3) 267-285 (1998).

35. J.F. Griffith et al., Toxic Appl. Pharmacol. 55 (3) 501-513 (1980).

36. H. Sasaki et al., J. Control. Rel. 27 (2) 127 -137 (1993).

37. Z. Liu et al., Drug Dev. Ind. Pharm. 31 (10) 969-975 (2005). PTE

267.22 C

266.11 C

230.82 C

96.77 C

91.40 C

80.78 C

288.55 C

79.79 C

DSC

50.00 100.00 150.00 200.00 250.00 300.00

Temp [c]

mW

0.00

-5.00

-10.00

-15.00

111.55 C

230.50 C

(e)

(d)

(c)

(b)

(a)

Figure 4: Differential Scanning Colorimetry thermogram

of (a) Pure Levofloxacin; (b) HPMC Methocel F4M;

(c) Optimized formulation LF5; (d) Gellan gum; (e)

Physical mixture of Levofloxacin, gellan gum and HPMC

Methocel F4M.


Ashley Roberts

DA

NLE

AP

/GE

TT

Y I

MA

GE

S

TROUBLESHOOTING

Biologics exhibit greater variability in stability testing

than do small-molecule drugs, and maintaining

a stable test environment is crucial.

Testing the Stability of Biologics

A number of factors can influence drug stability,

especially with highly-complex biomolecules. The

increased risk of instability requires more stringent

practices to maintain the stability of the drug product

throughout its shelf life. In addition, measures need to

be taken to minimize exposure to environmental factors

that can affect the integrity and efficacy of a product.

Kerry Bradford, analytical projects manager, and

Ashleigh Wake, biopharmaceutical services leader,

both at Intertek; Kim Cheung, senior director of quality

at Genzyme; and Niall Dinwoodie, global coordinator of

analytical testing, biologics testing solutions at Charles

River, spoke with Pharmaceutical Technology Europe

about the challenges in maintaining a stable

environment for biologics, how to determine shelf

life, the effects of upstream processing techniques on

the end product, and biologics versus small-molecule

drugs and the importance of stability testing.

Securing cGMP requirementsPTE: What standard methods are used

to ensure cGMP requirements during

stability testing?

Dinwoodie (Charles River): The standard

test methods for stability testing are, on the whole,

traditional quality control techniques for biologics.

They include size exclusion; ion exchange and reversed

phase high-performace liquid chromatography; sodium

dodecyl sulfate polyacrylamide gel electrophoresis

or capillary electrophoresis; potency assays; and

physicochemical measurements such as appearance,

pH, and particle size. Of these, particle-size

measurements are gaining increasing focus, but the first

test to fail is still often appearance.

Maintaining a stable environmentPTE: What are some of the challenges of

maintaining a stable environment

throughout testing?

Bradford and Wake (Intertek):

The main challenge here is the need for constant

monitoring. Modern stability chambers are able

to maintain conditions within the International

Conference on Harmonization tolerances with little

input, however, excursions caused by mechanical

failure need to be quickly identified in order to

prevent them from exceeding 24 hours. This requires

a 24/7 alarm system to monitor all chambers and a

dedicated team of staff to respond to emergencies

and fix any breakdowns.

Cheung (Genzyme): The biggest challenge

is controlling the condition of shipments, from

stability chambers to testing locations and storage

at these locations. Tracking chain of custody for

stability samples, and maintaining sufficient back-up

chambers and capacity ensures stability studies are

not impacted by equipment malfunction or physical

capacity constraints.

Dinwoodie (Charles River): Biologics present a

number of challenges in ensuring a stable environment

and comparability of results across time points. The

glass transition point for highly concentrated protein

products can occur within the normal operating range

of some freezers. While this is relevant to real storage

on the market, it can lead to a sudden change that has

no reflection on the period of storage. Also, for frozen

storage, consistency in thawing approaches are vital

for data comparison between time points.

Accelerated vs. real-timePTE: What are some of the advantages

associated with accelerated stability tests

vs. real-time stability tests?


According to the Arrhenius equation, samples undergo

the same degradation after 32 days at 25 °C as after

one year at 5 °C. There are obvious cost benefits

to accelerated time periods, particularly to quickly

eliminate poor candidates when at the early stages

of development of either a new drug substance, drug

product, or package. The accelerated tests can also

be used to submit early data to regulatory authorities;

however, accelerated storage data must always be

backed up with real-time data in the long term.

Cheung (Genzyme): Accelerated tests can

demonstrate comparability for material associated

with process changes in a shorter period of time

(e.g., six months) than long-term real-time studies.

The tests can assess whether a degradation profile

for an attribute is expected to be linear or non-



Presenters

Milton Boyer

Senior Vice President

of Drug Product

Manufacturing

AMRI

Moderator:

Rita Peters

Editorial Director

Pharmeceutical

Technology

EVENT OVERVIEW:

Outsourcing of all phases of pharmaceutical/biological devel-

opment and manufacturing continues to rise. As drug develop-

ment pipelines shift toward those requiring more complex and

specialized capabilities, quality agreements and communica-

tion planning to avoid non-compliance and the costly ramif-

cations are becoming more important. This webcast will review

the FDA draft guidance document Contract Manufacturing

Arrangements for Drugs: Quality Agreements and provide

insights from the contract manufacturing organization (CMO)

perspective into the integrated responsibilities and relationship

of the contract provider and the drug sponsor.

Key Learning Objectives

n Review FDA’s draft guidance document on Contract

Manufacturing Arrangements for Drugs: Quality Agreements

and the key takeaways about the high cost of non-compliance

and lack of quality agreements.

n Understand how heightened enforcement actions changing the

traditional relationship between the CMO and drug sponsor.

n Learn how strong CMO partners can help their pharmaceutical/

biotechnology partners avoid delays to market, specifcally

for drug development pipelines requiring more complex

and specialized CMO capabilities (e.g., biologics, biosimilars,

cytotoxics).

Sponsored by Presented by

Trends in Quality Agreements & Communications: A CMO Perspective

For questions contact Sara Barschdorf at [email protected]

On-Demand Webcast Originally aired June 23, 2015

Register for free at www.pharmtech.com/pt/cmo

Who Should Attend:

n Pharma/Biotech Companies

n Generic Pharmaceutical

Companies


Troubleshooting

linear. When temperature excursions

happen during transport, there is a

specific procedure that is followed

to determine whether the product

can be used or whether it must be

discarded. The accelerated data

are leveraged within that procedure

in which we’ve documented the

allowable excursion temperatures and

times during processing, shipping,

and handling, and the data are used

to respond to physicians’/patients’

questions about mishandling.

Dinwoodie (Charles River):

Accelerated tests are commonly used

to confirm that the test methods

being applied to the product indicate

stability. The methods are qualified

early on in a stability programme to

ensure that the real-time data reflect

the true stability of the product.

PTE: What are some of the

challenges or

disadvantages associated

with using accelerated

stability tests for the determination of

kinetic degradation?


While use of accelerated stability

tests in conjunction with Arrhenius

calculations is a good predictor of

degradation rates for straightforward

reaction kinetics, it does not account

for physical changes in the sample,

or more complex systems such as

emulsions and suspensions. For

example, elevated temperatures

may promote slight solubility of a

suspended drug particle, leading to

significant degradation that would

not occur in the equivalent room-

temperature sample.

Dinwoodie (Charles River):

Complex molecules such as biologics

rarely, if ever, obey the Arrhenius

equation. There are different

pathways for degradation to occur,

both chemically and structurally,

so no single degradation rate can

be determined. The accelerated

conditions will also influence the

degradation observed and may lead to

steps being missed or inappropriate

molecules being targeted as the

indication of degradation.

Stability testing and biologicsPTE: What factors are

involved in determining

shelf life?


Understanding the potential

degradation pathways of any biologic is

key to gaining a true shelf life. Achieving

this understanding is definitely

complicated by the structural diversity

of biologics. Regardless, if we are

working on an antibody, peptide, or

oligonucleotide, our general approach is

the same, and in many ways, weighted

before any sample is placed on stability.

During early stage development, the

material will be stressed under extreme

conditions of pH, temperature (60 ºC

is high), light, and oxidative conditions,

as well as physical forces such as

prolonged agitation, orientation of

storage, and freeze-thaw. The potential

pathways of degradation are then

evaluated using various analytical

techniques such as circular dichroism

(for higher order), Fourier-transform

infrared, nuclear magnetic resonance,

mass spectrometry, chromatography,

and electrophoresis.

The use of orthogonal approaches

is, where possible, always applied

in response to the complexity

of analytics. The final stability

programme is then designed based

on the results observed and the

potential degradation pathways

elucidated. Stability storage is then

initiated accordingly, remembering

that chemical/structural integrity is

not enough. All biologic evaluations

of potency upon storage should also

be documented. A simple box-ticking/

checklist approach does not work for

biologics, as what works for one will

not necessarily work for another.

PTE: Do upstream

processing techniques

have an effect on the

stability of end products?


The short answer is yes. However,

this is dependent on the drug and the

downstream process. A lot of this is

covered with assessment of the drug

product as well as substance.

Cheung (Genzyme): For biologics,

yes. For example, hold times of

upstream materials can impact critical

quality attributes and ultimately

affect the stability of drug substances

and drug products. Therefore,

stability studies are executed on all

intermediate production materials

held longer than 24 hours.

PTE: How does stability

testing of biologics and

small-molecule drugs

compare?


Issues associated with instability

are potentially more significant and

perhaps more likely to be observed

with biologics than their small-

molecule counterparts. Biologics

are inherently unstable, and this can

manifest in many ways, but what

differentiates them the most is their

tendency toward aggregation, a

phenomenon that is both frequently

observed and yet difficult to control.

Aggregation can present considerable

detrimental effects to the safety

as well as efficacy of a molecule.

Formulations are optimized to reduce

or at least slow down the process of

aggregation, but often, aggregation

is the predominant change to the

molecule observed on storage.

Cheung (Genzyme): Both stability

testing for large-molecule and small-

molecule drugs are important to ensure

that a product maintains specifications

throughout its shelf-life. For small-

molecules, critical quality attributes

and degradation products may be

better understood for each product

and shelf-life specifications for the

degradation products can be set based

on toxicology studies. In my experience,

there is more lot-to-lot consistency for

stability testing of small-molecules,

so interpretation of results is straight

forward. Also, in my experience with

biologics, stability testing encompasses

many more product attributes and

the degradation profiles may be

inconsistent from product-to-product

and/or lot-to-lot, making understanding

identified trends and interpreting results

more difficult. Test methods may be

more variable, again making it difficult

to interpret results.

Dinwoodie (Charles River): There

is less predictability for biologics.

Similar formulations of different

proteins can behave in a different

manner and have quite different shelf-

lives, and the concentration often

has a greater effect than it does for

small-molecule drugs. The industry has

seen many examples where process

changes have led to changes in the

stability of products that could not have

been predicted. The use of committed

stability tests for biologics is vital. PTE



PACKAGING FORUM

Hallie Forcinio is


Europe’s Packaging Forum

editor, [email protected].

Ensuring Correct Tablet CountElectronic counters are flexible and allow quick changeover between products.

Packaging of solid-dosage drugs generally occurs

by counting rather than by weight or volume.

Slat fillers remain commonplace, especially for large

batches. Demand is continuing to grow, however, for

electronic counters, which are now approaching slat-

filler speeds and tend to be more flexible.

“Flexibility to handle a wide range of products is

critical now,” reports Darren Meister, vice-president of

sales at IMA North America (Safe Division). This need

for flexibility also generates demand for counters that

are easier to clean and faster to change over. “Cleaning

and changeover are responsible for a lot of downtime

right now,” explains Meister.

Consistency is needed too. Programmed settings

ensure a product/count runs the same way each time.

Integrated quality control is another wish-list entry.

There is a focus on quality assurance to ensure correct

count and eliminate any broken or rogue doses.

Today’s countersToday’s electronic counters share several attributes:

flexibility, tool-less changeover, easy cleanability, and

faster speeds. The RX-12 Enhanced solid-dose counter

from BellatRx can be specified in single, twin, or quad

configurations to achieve speeds up to 240 bottles/

min (bpm). The flexible system handles solid doses

from 2–40 mm and containers from 1–4 in. Other

features include simplified product flow and tool-less

changeover (1).

The Countec DMC-60T Multi-channel electronic

counter, equipped with a 12-track counting tray and

twin filling nozzles, is handled in the United States by

Key International and counts up to 6000 tablets per

minute. The DMC series of counters have programmable

logic controllers, touch-screen operator interfaces,

and infrared and LED optical sensors with dust-

sensing windows. The sensors detect each dose on

multiple planes so data can be analyzed from each

object that passes. “The machine collects data about

the wholeness of the tablet or capsule and checks

if multiple doses are falling past at the same time,”

explains Jonathan Braido, marketing manager at Key

International. Dark-time adjustability helps detect broken

or double tablets. “If the Countec machine identifies

a broken tablet, it will trace the dose to a bottle, then

reject the bottle,” reports Braido. The flexible Countec

unit handles metal, glass, or plastic containers up to

120 mm in diameter. Large access areas, tool-less

disassembly, quick-release connectors for product-

contact parts, perforated stainless-steel product feeding

trays for dust and chip collection, and dust-collection

ports expedite cleaning and changeover. “It will usually

take about an hour to fully clean the machine,” says

Braido. Changeover to a different container (same

product) involves a few minutes to change container

funnels and make a few tool-less adjustments.

IMA’s SwiftPharm 2 (SP 2) counter is a second-

generation, high-speed machine. Dust-immune

electrostatic field sensors replace the photoeyes or

optics used by competing systems. The electrostatic

field sensors not only ensure accurate counting, but

also increase uptime because there’s no need to stop

the line mid-run to clean the sensor when handling

extremely dusty products. In operation, the falling

product disturbs the field. Measuring this disturbance

allows the detection of overlapping product as well

as the differing mass of broken pieces so bottles

containing fragments can be rejected. In addition,

an optional dual-sensor configuration provides a

redundant count. Both sensors must agree each dose

is correct and properly counted. IMA also equips its

counters with machine-vision systems built by Antares

Vision. Cameras mounted over the trays detect broken

and chipped doses as well as rogue product. Tool-

less disassembly means one operator can remove all

product-contact parts, clean the machine, and install

another set of product-contact parts so the counter

can run while the first set of product-contact parts is

being cleaned. This changeover requires as little as 30

minutes. When changeover only involves a different

container size (product remains the same), changeover

time can drop to less than five minutes.

The next generation CFS-622*4 tablet counter from

NJM Packaging offers cleanability, quality control, and

onboard inspection. The CFS-622*4 tablet counter can

be equipped with a CountSafe inspection system from

Optel Vision plus an automated rejection system. The

system features a two-axis linear robot that can be

adapted and integrated to Cremer electronic counters.

The tool-less ejector rejects defects: wrong shape,

wrong colour, wrong size, broken product, or rogue.

Different alarm levels make it possible to stop the

line if a rogue product is detected, but simply reject

the fragment, if a broken solid dose is located. The

vacuum-reject arm captures any flawed solid-dose

product before it falls into a container and deposits

it into a closed bin. Virtually all other inspection

systems reject filled containers with a flawed solid

dose, resulting in considerable rework or waste. A

preseparator collector and HEPA filter prevent the

escape of any substance or dust.

The intermittent-motion Cremer CFS-622*4 tablet

counter consists of four modules. It relies on a

feedscrew for container transport and reaches speeds

up to 200 bpm. A continuous-motion model, the

Cremer CFI-622 tablet counter, can be configured with

up to 10 modules, handles containers with starwheels,

and reaches speeds up to 400 bpm.



Packaging Forum

A servo-motor-driven mechanical vibration system

eliminates the mechanical springs used in other vibratory

systems. The result is a stable and controlled movement

of the solid dose, which provides the consistent action

needed for a camera inspection and efficient counting

accuracy. “Proper separation and delivery of the product

into the container are key to having an accurate count,”

explains Mark Laroche, vice-president of sales at NJM

Packaging.

In addition, a patented system, which relies on linear

servo technology, feeds tablets out of the hopper.

Changeover to a new bottle (same product) takes 10–15

min. Cleaning in preparation for filling another product can

be accomplished in as little as 20–25 min, depending on

standard operating procedures. Product-contact parts can

be removed without tools, leaving a simple-to-clean frame.

To further reduce line clearance time, NJM Packaging

offers the TFE (tablet-free entrapment) conveyor (see

Figure 1). Generally installed after the counter, it eliminates

the time-consuming task of disassembling or removing

the conveyor chain between runs to check for trapped

products. The TFE conveyor chain drops down for tablet

recovery, and integral windows and lights help operators

see any trapped tablets inside the conveyor.

Monoblock systems also are available and offer a

high level of flexibility. IMA’s four-in-one Uniline machine

integrates desiccant dispensing, solid-dose counting,

cottoning, and capping on a single base (see Figure 2).

Changeover occurs with the push of a button.

Uhlmann’s Integrated Bottle Center can integrate counting

and capping with desiccant feeding, cottoning, and induction

sealing, plus inspection systems such as cameras and metal

detectors. Options include the IBC 120 model (capable

of speeds of 150 bpm) and the faster IBC 240 machine

(240 bpm). The IBC 120 model handles a slightly broader

container range with volumes from 30–1500 cc, diameters

from 25–125 mm, and heights from 45–200 mm (2).

Romaco also supplies integrated systems with

Romaco Bosspak RTC Series or VTC Series counters as

the centerpiece (3). The RTC counters feature rotary

continuous-motion container filling and tool-less

changeover. Positive tablet/capsule separation and

vibration-free stream filling help ensure products enter the

container singly and maximize count accuracy. A range of

models offer one, two, four, or 12 counting stations and

speeds from 15–200 bpm (4).

At the opposite end of the solid-dose counting spectrum,

there are smaller units for quality control (QC) counts, stock

checks, and short runs. Kirby Lester’s latest standalone

tablet counter, the KL1 model, features a reduced footprint,

fast counting speed, and interchangeable product-contact

parts. Sharp Packaging Solutions purchased seven units

plus product-contact parts for each product it runs to

perform hourly QC checks on all bottling lines and small

quantity bottle filling. Return on investment is expected

within 10 months (5). Patented optic sensing technology

“sees” doses falling past the batch sensors to count up

to 15 doses/sec. After completing the count, the tablets/

capsules are emptied from the KL1’s clear tray into a

waiting bottle or vial. Cleaning takes approximately 60

seconds. The entire pill path is removable for cleaning with

soap and water or alcohol and a lint-free cloth.

Another small unit designed to confirm counts, the

Countec DMC-CQ2 tablet verification counting machine from

Key International, “can replace a visual count inspection and

ensure quality of the tablets or capsules,” reports Braido.

Suitable for quality checks on the packing line or in the lab,

the counter handles tablets or capsules of any shape or

size and counts up to 9999. An easy-to-use touchscreen

with a built-in printer supports QC and data management.

An adjustable container platform accommodates different

bottle heights and diameters.

Selecting a counterSelecting the best counter for an application involves

many considerations. First and foremost, “Understand

what you want to accomplish,” advises Laroche of NJM

Packaging.

Braido notes that other questions to be asked include:

What products are to be handled (e.g., tablets or

capsules)? Is the product coated or uncoated? Dusty or

not dusty? How big are the batches to be handled? How

many counted tablets and/or bottles/minute are needed

for your production line?

“If the machine is changing over three times a day, an

electronic counter is better suited,” says Meister of IMA

Pharma. “If one product runs all day, a slat counter might

make the most sense.”

Figure 1: NJM Packaging’s TFE (tablet-free entrapment) conveyor design minimizes line clearance time. Photo is courtesy of NJM Packaging.

Figure 2: Monoblock machines, such as IMA’s Uniline system, combine multiple functions on one base to enhance flexibility and reduce floor space requirements. Photo is courtesy of IMA.



PharmTech.com

NOVEMBER 2014 Volume 26 Number 11

MARKET REPORT

Germany Post AMNOG

TECHNICAL Q&A

Continuous Manufacturing

PEER-REVIEWED

Sublingual Formulations

QbD in

Parenterals

Addressing

Particulate

Contamination

Advancing Development & Manufacturing

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Packaging Forum

“Machines also should be user-friendly for operating,

cleaning, and changeover,” says Braido. Other

considerations include bottle sizes, cost and labour

requirements, room size, and changeover complexity and

related downtime. Many pharmaceutical manufacturers

and contract packagers specify a counter with dedicated

product-contact parts. “They need a solution where

they can swap out the entire ‘pill path’ to eliminate any

chance of cross-contamination between counting runs

of different medications,” explains Mike Stotz, senior

marketing manager at Kirby Lester. “They want to change

these parts out quickly, clean them easily, and store them

for specific NDC [National Drug Code] batches.”

Specifications also must consider integration

with upstream and downstream equipment and

communication between machines so stop and restart

signals can be sent when problems arise and are cleared.

It’s also important to plan sufficient accumulation

between machines to prevent downtime for minor faults.

“You don’t want the counter to stop because it’s waiting

for bottles, nor do you want containers backing up into

the filler due to a downstream slowdown or stoppage,”

says Meister.

Finally, is onboard inspection needed? “Inspection of

tablets has been a number one wish-list item for a long

time,” reports Laroche. However, onboard inspection can

slow production speeds, and small, acceptable variations

have been known to cause false rejects.

What’s next?New technologies will be able to count and fill even faster

and more efficiently. “Future counting machines will be

easier to operate, which leads to less user error and will

provide better data management capabilities,” says Braido.

Meister predicts we’ll see more counters equipped with

inspection systems. “There’s always the push for more

quality,” he explains.

Laroche agrees. “Inspection is what customers

are requesting. It will take a while, but once we start

seeing integrated inspection systems, it will become a

requirement.”

References1. BellatRx, “Rx-12 Enhanced,” www.bellatrx.com/newsletter/

News-06-2014.html, accessed 5 May 2015.

2. Uhlmann, “Integrated Bottle Center 120,” Machine Product

Information, http://fileadmin.uhlmann.de/fileadmin/

Redakteure/Info_Download/Produktinfo/EN/integratedbottle-

center120.pdf, accessed 19 May 2015.

3. Romaco, “Romaco Tablet and Capsule Counting Machines—

Suited for All Requirements,” www.romaco.com/pharma-

tablet-counting-solutions, accessed 21 May 2015.

4. Romaco, “RTC Series from Romaco Bosspak,” www.romaco.

com/romaco-bosspak-rtc-series, accessed 21 May 2015.

5. Kirby Lester, “Pharma Packager: QC Time Reduced by 50%,”

Case Study, www.kirbylester.com/case_study/Case_Study_

Sharp_Pkg_Services_PA_KL1.pdf, accessed 8 May 2015. PTE

Ad IndexCOMPANY PAGE

AbbVie ...................................................................................... 11

Albany Molecular Research ...................................................45

Angus ....................................................................................... 19

BASF .........................................................................................31

Catalent Pharma Solutions ....................................................52

Clinigen Group Plc ................................................................... 51

Corden Pharma Intl Gmbh ..................................................... 15

CPhI Korea ................................................................................33

Dow Europe Gmbh ..............................................................2, 23

Pet Flavors Inc ......................................................................... 13

Powder Systems Ltd .................................................................5

Sepha ....................................................................................... 17

SGS Life Science Services ......................................................39

Shimadzu Europe ......................................................................9

Vaisala ......................................................................................29

Veltek Associates Inc ................................................................7

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